Tuesday, 02/07/2023

Funded Technologies

Project Title Principal Investigator Project Abstract Project Start Institution Center / Hub Technology Type Product Indication Licensing Status Point of Contact
Nutrient Data API to support mobile health applications Lisa Harnack, DrPH, RD, MPH To create global access to the University of Minnesota Food and Nutrient Database™ through development of an application programming interface (API) in order to meet software developer needs for a comprehensive, complete, up-to date, and reliable food and nutrient database to support patients living with nutrition-related chronic diseases. 01/01/2016 University of Minnesota MN-REACH image of external link icon Health IT Application programming interface of comprehensitve nutritional database for mHealth developers Nutrition-related chronic disease Available Andrew Morrow
3D Shoulder Motion Measurement Device (The MnMotion System) Paula Ludewig, PhD PT To develop a cost-effective, accurate, precise, and objective 3-dimensional motion measurement for clinicians treating patients or athletes with shoulder pain or motion disorders. 01/01/2016 University of Minnesota MN-REACH image of external link icon Diagnostic device, Combination Product including mHealth product and research tool A three dimensional shoulder motion measurement system that integrates with readily available smartphone technology Musculoskeletal or neurologic movement disorders, initially specific to shoulder joint dysfunctions Available Andrew Morrow
Neuromodulation for Intractable Sleep disorders Gregory Molnar, PhD The proposed product is a software suite to diagnose sleep architectures using DBS electrodes implanted in PD patients and modulate sleep via electrical stimulation through those same electrodes. The software and algorithms we will develop could be uploaded into existing DBS systems to expand the therapy and thereby improve sleep symptoms in PD. 03/01/2017 University of Minnesota MN-REACH image of external link icon Therapeutic Device Deep brain stimulation Sleep disorders in Parkinson's disease Available Andrew Morrow
Continuous lactate monitor for early indication of resuscitation in trauma and sepsis Elliot Botvinick High mortality rates continue to persist in many patients with critical conditions such as sepsis, and trauma. Treatment in these cases is often aimed at stabilizing patient parameters such as vital signs. However, by the time these parameters change, it is often too late to intervene effectively. A compendium of evidence over the last few decades has shown that lactate concentration is one of the most powerful early predictors of outcome in many critical conditions, and that lactate concentration can be used to improve patient survival by directing therapy more effectively. Lactate-guided therapy is difficult or impossible to utilize in clinical practice however because current technologies allow only intermittent lactate measurements, thus failing to provide adequate and timely information about lactate changes. As such, a continuous measurement of lactate is desired to provide real-time lactate concentration. This project advances the development of our technology that will provide hands-free continuous lactate monitoring. 03/01/2015 UC Irvine UC-CAI image of external link icon Diagnostic Device Real-time lactate measurement Lactate Monitoring for sepsis and trauma Available Casie Kelly
Development of a Self-Regenerative Hybrid Heart Valve Arash Kheradvar This research aims to develop and test the first hybrid tissue-engineered heart valve. The hybrid heart valve leaflets are composed of a super-thin mesh of Nitinol that is tightly enclosed by multiple layers of patient’s own cells making a living implant possible within the heart. 03/01/2015 UC Irvine UC-CAI image of external link icon Therapeutic Device Self-Regenerative Hybrid Heart Valve Heart Valve Disease Available Casie Kelly
Bio-Inspired Transcatheter Mitral Valve Arash Kheradvar This project will develop and test the first transcatheter mitral valve with dynamic annulus, and its delivery system for transapical implantation. This bio-inspired mitral valve system will offer most of the advantages that a native mitral with dynamic annulus has to offer for left ventricular function. 08/01/2015 UC Irvine UC-CAI image of external link icon Therapeutic Device Transcatheter Mitral Valve Heart Valve Disease Available Casie Kelly
Optical platform for rigid, high-throughput screening of cellular mechanotransduction Vasan Venugopalan The initiation and/or progression of numerous pathologies has been linked to the dysregulation of cellular mechanotransduction. These pathologies include arteriosclerosis, hypertension, cardiomyopathy, and asthma which are relevant to the mission of NHLBI. We aim to develop and deploy a novel high-throughput screening (HTS) technology, that is compatible with standard image cytometry based HTS platforms, to screen for the efficacy of compounds to modulate cellular mechanotransduction processes in 2D cell cultures. Our objective is to use our technology to identify drugs that display the ability to modulate mechanosignaling as opposed to biochemical activity alone. 08/01/2015 UC Irvine UC-CAI image of external link icon Diagnostic Device/Tool Optical platform for rapid high-throughput screening of cellular mechanotransduction Arteriosclerosis, Hypertension Available Casie Kelly
Detection of Thrombin Generation for Acute MI Monitoring Charles Craik, PhD Developing peptide based technology activated by thrombin at sites for blood coagulation for imaging and detection of blood clots 08/01/2015 UCSF UC-CAI image of external link icon Diagnostic Device Diagnostic for imaging of blood clots Acute Coronary Syndrome Available Catherine Smith
Oral solid dosage formulation of Cholera toxin B subunit Krystal Hamorsky Ulcerative colitis (UC) is an emerging global health problem effecting approximately 1.25 million individuals across the major markets. Although no cure is yet available for UC, there are several treatment options to induce and maintain remission of severe intestinal inflammation. However, commercially available therapeutics have limited effectiveness, variable response and adverse side effects; therefore there is a clear unmet need for new and improved therapeutics. We envision that our proposed technology, dry-formulated plant-made cholera toxin B subunit (CTBp), will be a novel, safe, effective and patient-accepted UC treatment. We have demonstrated that oral administration of CTBp mitigates UC in a mouse model, by facilitating mucosal wound healing via the preclinical study, a liquid CTBp formulation was administered orally after neutralization of gastric acid by preadministration upregulation of TGFb signaling pathways. For that of a large volume of bicarbonate containing solution because the protein is acid labile. This is problematic in terms of patient acceptance and targeted delivery. Herein, we propose to develop dry-formulated CTBp, the attributes of which include effortless formulation for targeted delivery, ease of administration and higher patient acceptance, which will in turn help assure higher treatment compliance in chronic therapy scenarios. Successful development of an effective CTBp dry-powder form will be achieved in tasks leading to three milestones, each encompassing discrete go/no]go decisions: 1) Identify up to three optimal in tasks leading to three milestones, each encompassing discrete go/no-go decisions: 1) Identify up to three optimal CTBp powder formulations; 2) Identify a stable and capsule-compatible powdered CTBp Drug Substance; and 3) Determine the oral efficacy of the prototype CTBp Drug Product. Completion of all three milestones will provide strong proof of principle of the dosing advantages and wound-healing efficacy of orally administered solid dosage CTBp. The development and demonstration of this technology is a critical step towards commercialization of our CTBp for human therapeutic use. No products currently available for UC or in development possess the combination of attributes that our product would offer. We anticipate that the combination of CTBp's unique wound healing effect and the convenience of a solid dosage form will represent a highly desired first-in-class treatment with the potential to transform UC standard of care. 03/01/2016 University of Louisville UofL - ExCITE image of external link icon Biologic Drug Plant-made Cholera toxin B subunit Ulcerative colitis Available Chris Barton
Colo-miR: a plasma microRNA assay with high specificity and sensitivity for colorectal neoplasm diagnosis Susan Galandiuk In the US, approximately 140,000 patients are diagnosed annually with colorectal cancer (CRC), with approximately 51,000 CRC deaths annually.1 Many deaths could be prevented if precancerous polyps were detected with screening and removed prior to development of invasive cancer. If found early, CRC may be cured; once symptoms develop, the cure rate falls to less than 50%. Current methods for diagnosis include colonoscopy and flexible sigmoidoscopy and less-invasive diagnostic methods such as fecal occult blood tests, DNA-based stool tests, and plasma-based assays. However, these methods are limited in that they are either expensive, require bowel preparation and sedation, can be associated with medical complications, require stool specimens, or have low sensitivity and specificity. A minimally invasive method for early diagnosis with high sensitivity and specificity will greatly improve early clinical diagnosis and patient compliance. The envisioned product is a diagnostic point-of-care platform based on magnetic micro-bead extraction and electrochemical detection of a clinically-proven, proprietary panel of 7 plasma miRNAs (Colo-miR) that is capable of distinguishing patients with colorectal cancer from patients without cancers with 90% sensitivity and 100% specificity as well as distinguish patients with colorectal polyps from individuals without polyps or cancers with 65% sensitivity and 95% specificity. This technology is better than existing products in that Colo-miR may identify individuals with benign or malignant colorectal neoplasms. For this project, we will develop and fabricate two platforms: 1) a miRNA extraction device; and 2) a point-of-care device based on electrochemical detection, to isolate and quantify, respectively, the proprietary 7-miRNA panel and 2 housekeeping miRNA. In addition, the miRNA extraction device can be used as a stand-alone device, as well as integrated into the point-of-care device, to improve miRNA extraction efficiency and selectivity, while reducing processing time and costs associated with the current Colo-miR assay. Milestones: 1) External validation and data analysis of Colo-miR panel; 2) Streamlined Colo-miR extraction device; and 3) Development of point-of-care device. Deliverables: · Proprietary technology for both Colo-miR biomarker extraction and a point-of-care assay for colorectal polyp (cancerous and benign) diagnosis. · Initial revenue generation will involve licensing our product with an interested company. Team Strengths: Our team includes a colorectal surgeon, bioengineer, and biostatistician. The colorectal surgeon performs ~300 colonoscopies per year and has worked on the FDA Center for Devices and Radiological Health Medical Devices Advisory Committee, General and Plastic Surgery Devices panel. The bioengineer has extensive experience with development of micro-total analysis systems; has been involved in the formation of three start-up companies; and holds 6 issued patents & 6 patents pending in microtechnology-based devices. Our biostatistician has experience with miRNA expression, biomarker development, and gene signatures and has worked closely with the PI on the prediction model and blinded data analysis. 10/01/2016 University of Louisville UofL - ExCITE image of external link icon Diagnostic Device miRNA-based diagnostic & device Colorectal cancer Available Chris Barton
Avaren-Fc lectibody for liver graft protection against hepatitis C virus infection Nobuyuki Matoba The goal of this project is to develop a new biologic drug for liver transplant recipients with chronic hepatitis C virus (HCV) infection. HCV poses a major health problem, with 3 to 6 million individuals infected in the USA and >180 million worldwide. HCV infection often leads to chronic liver disease, which can cause cirrhosis and death from either cirrhosis or liver cancer. Consequently, HCV-related end-stage liver disease is the leading indication for liver transplantation (LT) and will remain so in coming years, because many HCV-infected individuals are unaware of infection until severe liver complications ensue. Currently, ~3,500 HCV-associated LTs are performed in the USA per year. After patients undergoing LT, antiviral therapy based on currently available drugs is not commenced until the graft liver function becomes stable, which could take ~6 months post LT. As a result, recurrent HCV infection is a universal problem, increasing the risk of accelerated cirrhosis, graft failure and death. Hence, prevention of liver graft infection is a significant unmet need in HCV treatment. Our proposed solution is a chimeric antibody-like antiviral protein, Avaren-Fc lectibody, which would be infused during and after LT so that the graft liver is protected from HCV. Unlike currently approved HCV drugs, which limit viral replication in infected liver cells, the lectibody can potently inhibit HCV before infecting target cells, providing an opportunity to inactivate the virus in LT patients without damaging newly grafted livers. Additionally, unlike other similar products under clinical development, Avaren-Fc lectibody is efficiently bioproduced in plants and exhibits potent inhibitory activity against HIV and cancer cells, in addition to HCV. Hence, if the safety and efficacy of Avaren-Fc is demonstrated for the proposed use, the product may also offer a new treatment option for HIV/HCV co-infection (which represent 10-15% of the 3-4 million chronic HCV infections in the USA) and HCV-associated liver cancer (which represent ~50% of 29,000 liver cancer cases per year in the USA). To facilitate the preclinical development of Avaren-Fc lectibody, this two-year project will perform basic safety and efficacy studies in preclinical rodent models in collaboration with qualified contract research organizations. The combined expertise of our project team covers drug development, clinical and regulatory aspects that are necessary to bring Avaren-Fc to the clinic. The project has three milestones, each encompassing a discrete go/no-go decision point: 1) Identify an optimal Avaren-Fc formulation for intravenous administration; 2) Identify a maximum tolerated dose in rats; and 3) Determine the HCV inhibitory activity in a mouse model. Completion of all three milestones will provide strong proof of principle for the development of Avaren-Fc towards a Phase I clinical trial to protect transplanted livers in patients with HCV-related end-stage liver disease. 03/01/2017 University of Louisville UofL - ExCITE image of external link icon Biologic Drug Avaren-Fc lectibody Hepatitis C Available Chris Barton
Topical application of CTBp for oral mucositis Nobuyuki Matoba ""Oral mucositis is a common non-hematological complication of chemo/radiotherapy for cancer. It is characterized by swelling, erosion and ulceration of oral mucosa, often causing severe pain, oral dysfunctions and hospitalization and thereby disruption of ongoing cancer therapy. It is estimated that 30 40% of patients undergoing cancer treatment suffer from oral mucositis, corresponding to over 400,000 people per year in the United States. Currently, supportive care based on analgesics, anti-inflammatory agents and oral hygiene maintenance is the primary treatment. No topical drug that can facilitate the healing of the damaged mucosa is available, representing a significant unmet need in the management of oral mucositis. Our proposed solution is topical application of a cholera toxin B subunit variant produced in plants (CTBp). We envision that CTBp could be formulated in a mouthwash solution or a gel to facilitate oral mucosal healing, and may be coformulated with other available supportive care agents. CTBp is currently being developed by our group as an oral therapy for ulcerative colitis based on the proteins unique muco-adhesive activity leading to epithelial wound healing. Since the entire alimentary tract shares a common epithelial repair mechanism, CTBp is anticipated to facilitate the restitution of the damaged oral mucosa. Importantly, such mucosal healing activity is not attained by native CTB of Vibrio bacteria because of the lack of a critical, artificially introduced amino acid sequence within CTBp, highlighting the advantageous feature of our plant-made protein. To establish the feasibility of CTBp for the proposed indication, this 1-year project will test the proteins therapeutic potential in animal models of mucositis. We will first employ a well-characterized acute radiation-induced mucositis model in hamsters. This pivotal study will be outsourced to an experienced contract research organization (Milestone 1), with the results providing the first Go/No-go decision point of this project. If CTBps therapeutic effect is demonstrated, we will next employ a mouse chemotherapy-induced mucositis model to obtain additional in-depth efficacy data. Additionally, we will test CTBps potential impacts on the anti-tumor activity of 5-fluorourasil, a widely used chemotherapeutic agent that often causes mucositis in cancer patients (Milestone 2). The outcome of this safety study will provide the second Go/No-go decision point of this project. Should the proposed studies demonstrate CTBps efficacy and safety in the animal models, the results will justify further preclinical studies towards a first-in-human clinical trial. The proposed team is led by Drs. Nobuyuki Matoba and Krystal Hamorsky, who have invented the CTBp technology and are specialized in biopharmaceuticals development. Their ongoing CTBp preclinical safety and efficacy studies as well as bioanalytical methods and formulation development in the ulcerative colitis project will significantly and synergistically facilitate the proposed research."" 08/01/2017 University of Louisville UofL - ExCITE image of external link icon Biologic Drug Plant-made Cholera toxin B subunit Oral mucositis Available Chris Barton
Preparing Heart and Mind: A Mobile & Web Application for Expectant Parents & Health Care Providers After Fetal Heart Disease Diagnosis Anne McKechnie, PhD RN To support, educate, and connect parents during pregnancies with fetal abnormalities to content and care providers in order to reduce stress and prepare for neonatal care. 04/01/2016 University of Minnesota MN-REACH image of external link icon Health IT mHealth application to support, educate, and connect parents during pregnancies with fetal abnormalities Parents during pregnancies with fetal abnormalities Available Chris Ghere
Clinical Validation of an Unbiased Next-Generation Sequencing Diagnostic Assay for Pneumonia in a CLIA-Certified Laboratory Charles Chiu MD, PhD More than 30% of cases of pneumonia in hospitalized patients remain undiagnosed despite extensive conventional testing. Failure to diagnose these serious infections in the timely fashion leads to ongoing nosocomial transmission and increased mortality. This project is focused upon the development of a rapid unbiased assay for diagnosis of pneumonia in a CLIA certified facility. The data will also be analyzed to identify all of the pathogens. As such it will enable appropriate treatment decisions and further understanding of pathogen etiology in pneumonia. 08/01/2014 UCSF UC-CAI image of external link icon Diagnostic Device Assay for diagnosis of pneumonia Pneumonia Available Darya Bubman
Nano-engineered, non-thrombolytic small diameter synthetic vascular grafts Tejal Desai, PhD Developing non thrombogenic small caliber synthetic vascular graft comprising of nano-engineered surfaces to decrease compications associated with synthetic vascular grafts 03/01/2015 UCSF UC-CAI image of external link icon Therapeutic Device Synthetic Vascular graft comprising nano-engineered surfaces Coronary artery or peripheral artery disease Available David Fung
Data Fusion and Analytics to Predict In Hospital Cardiopulmonary Arrest and Reduce Alarm Fatigue Richard Fidler and Xiao Hu Developing the Patient Chronology System and SuperAlarm Algorithm including establishing front end usr interfaces of Patient Chronology System and SuperAlarm Algorithm including establishing front end user interfaces of Patient Chronology and refinementof the backend to improve accuracy and eliminate unnecessary patient alerts 08/01/2016 UCSF UC-CAI image of external link icon Combination Product Hospital Alarm Algorithm Prediction of Cardiopulmonary Arrest and Cardiopulmonary Instability Available David Fung
HEAL - High Efficiency Artificial Lung Shuvo Roy and Benjamin Padilla Development and optimization of the high efficiency artificial lung (HEAL) prototype device and conducting of in vitro and in vivo studies to test feasibility of obtaining desired oxygen transfer rates with use of minimal amounts of anticoagulant. 08/01/2016 UCSF UC-CAI image of external link icon Therapeutic Device Artificial Lung Acute Respiratory Failure Available David Fung
Erythroferrone antibodies and assays to support drug development for anemia and iron disorders Tomas Ganz, PhD, MD The project is focused on the development of antibodies against erythroferrone, a newly discovered regulator of iron metabolism. These antibodies will have likely utility for the differential diagnosis of anemias and iron overload disorders, and as companion diagnostics for new agonists and antagonists of the erythroferrone pathway that are under development. 08/01/2014 UCLA UC-CAI image of external link icon Diagnostic device Erythroferrone assay for anemia and iron disorders anemia and iron disorders Available Earl Weinstein
Preclinical and Clinical Studies of a Novel Read-Through Drug Capable of Restoring Cardiac and Muscle Function in Duchenne Patients Carmen Bertoni, PhD Duchenne muscular dystrophy (DMD) is the most severe of the neuromuscular disorders and affects 1 in 3500 newborn males. Approximately 13% of the mutations that cause DMD are nonsense mutations that lead to lack of dystrophin. The affects skeletal and cardiac muscles and is characterized by progressively loss of ambulation and premature death by cardiac or respiratory failure by the age of 30. Pulmonary symptoms also develop, such as shortness of breath and fluid accumulation or congestion in the lungs. This project will focus at developing and optimizing a drug capable of suppressing nonsense mutations and restore normal, full-length dystrophin expression. The same drug could also be used to treat virtually any genetic disease known to be caused by nonsense mutations (30% of the genetic disorders known to date). 08/01/2015 UCLA UC-CAI image of external link icon Small molecule drug RTC for Duchenne Muscular Dystrophy DMD patients characterized by premature termination codons in the dystrophin gene. Available Earl Weinstein
Noncrushable Pills for Prevention of Opioid Abuse Heather D. Maynard, PhD Drugs like oxycodone are misused by crushing or liquefying pills for immediate dosage, causing a euphoria, which perpetuates abuse. Few robust abuse deterrent formulations are currently FDA approved. The proposed research prevents illegal use of such prescription drugs by encapsulating the drug within a biodegradable elastomer that is unable to be crushed or liquefied and will also be stable to microwaving and freezing, which many current formulations are not. The drug will only be released in the stomachs of patients who take the pills as intended. 10/01/2015 UCLA UC-CAI image of external link icon Drug Delivery/Therapeutics Noncrushable Opioid Pill Oxycodone abuse prevention Available Earl Weinstein
Peripherally restricted cannabinoids for chronic pain Igor Spigelman, PhD Chronic pain represents a major socioeconomic and clinical challenge, in part because even the most efficacious of the currently available remedies are limited by their side effects. We developed synthetic peripherally-restricted cannabinoids (PRCBs) that don’t cross the blood-brain barrier, thereby providing pain relief without the side effects associated with central nervous system (CNS) cannabinoid receptor activation. These PRCBs are the first in their class to exhibit potent and repeated suppression of chronic pain symptoms, without development of tolerance, and with a complete lack of CNS-mediated side effects. Their effectiveness was demonstrated in widely used rodent models of chronic pain induced by peripheral nerve injury, burn injury, or chemotherapeutic drugs, and in cancer pain, where PRCBs also showed anti-tumor properties. Clinical implementation of PRCBs for treatment of targeted patient populations could provide relief of their chronic pain and suffering without affecting mental acuity, motor coordination, or memory. This project aims to conduct several crucial investigational new drug enabling studies including FDA-compliant assessment of safety pharmacology and toxicology, as a prerequisite to clinical implementation of PRCBs. 10/01/2015 UCLA UC-CAI image of external link icon Small molecule drug Peripherally-restricted cannabinoid (PRCB) Chronic pain Available Earl Weinstein
Selective targeting of TGF-β activation for airway remodeling with engineered monoclonal antibodies Stephen Nishimura MD Chronic obstructive pulmonary disease (COPD) is now the third leading cause of death in the United States (2) Current treatments provide incremental palliative benefit in COPD patients. There are currently no therapeutics which have been demonstrated to change the course of the disease. This project focuses on developing diagnostic and therapeutic antibodies which target TGFb mediated inflammation and fibrosis in COPD. These will be used to identify the sub-populations of COPD patients where modification of TGFb activation has the greatest potential impact and to develop a TGFb activation targeted therapeutic. 08/01/2014 UCSF UC-CAI image of external link icon Biologic Drug Monoclonal Antibodies TGF-beta Available Ellen Kats
Lung Assist Device Abbas Ardehali, MD Patients with acute lung failure who are refractory to mechanical ventilation have poor prognosis and utilize significant healthcare resources. Veno-venous Extra-Corporeal Membrane Oxygenation (vv-ECMO) is being increasingly used to salvage such patients, as accumulating data indicate that it is effective and may improve survival. However, the currently used vv-ECMO catheter has two major shortcomings that render it subject to positional changes and re-circulation of oxygenated blood, thereby affecting its efficiency. This project will develop a newly designed/improved catheter system for patients in respiratory failure in need of vv-ECMO. 08/01/2015 UCLA UC-CAI image of external link icon Therapeutic Device vv-ECMO Catheter Patients in respiratory failure in need of veno-venous Extra-Corporeal Membrane Oxygenation Available Emily Loughran
VisiTube Robert Cameron, MD Pleural chest tube placement performed routinely for fluid and/or air collection inside the chest can have significant complications and even result in patient deaths. This project will develop a video-guided device that provides physicians with visual aid during the chest tube insertion process, greatly reducing the risk of pneumothorax. 08/01/2015 UCLA UC-CAI image of external link icon Therapeutic Device Video-guided chest tube pleural effusion, hemothorax, chylothorax, and empyema (fluids) or pneumothorax (air) Available Emily Loughran
Non-invasive real-time assessment of coronary stenosis using RBCAGE Eric Berson The PIs have developed a non-invasive technique for quantifying the severity of stenosis (blockage) in coronary arteries. Dr. Eric Berson is an expert in fluid modeling and computational fluid dynamics. Dr. Shahab Ghafghazi is a cardiologist with expertise in developing clinical studies necessary for validating this technology and guiding it towards commercialization. One million invasive coronary angiography (ICA) procedures are performed every year in patients who present with chest pain or are known to have stable coronary artery disease (CAD). The goal of the procedure is to determine if there is any significant blockage (stenosis) that limits blood flow to the heart muscle in the coronary arteries. Almost half of ICAs culminate in stent placement in coronary arteries in order to relieve the blockage of blood flow. The cardiologist performing the procedure in the catheterization lab determines the significance of the stenosis by one of two methods: either by visually estimating the degree of stenosis (‘eyeballing’ the stenosis), which is the routine practice and is done in the majority of patients, or by invasively measuring fractional flow reserve (i-FFR), which is the Gold Standard test that has been demonstrated to both improve patient outcomes and diminish the cost of healthcare. However, i-FFR is only performed in 10-20% of patients because it is invasive, expensive, and time-consuming, and requires more radiation and contrast exposure. Our technology provides an accurate, highly sensitive, non-invasive method to assess the significance of coronary stenosis through coronary angiography without i-FFR measurement. When performed in real-time (within 5 minutes), this allows the cardiologist to make an informed decision regarding stent placement. Notably, such a method would deliver the benefits of i-FFR measurement in terms of cost savings and improvement in patient outcomes, while simultaneously avoiding the disadvantages such as extra cost for the procedure and time burden. These funds will be used to: fully develop a correlation between our RBC AGE and i-FFR by conducting a retrospective study in 50-100 patients with known CAD who have already undergone coronary angiography & i-FFR (Milestone 1); achieve real time processing (Milestone 2); and develop dedicated software that integrates rendering and modeling with a user friendly interface to be used in future prospective studies (Milestone 3). The key go/no-go pivot point is to achieve a strong correlation with i-FFR in a retrospective study. If the retrospective study passes the go/no go test, the technology will be proven and ready for commercialization, and we are open to licensing the technology at that point. We aim to accomplish this within 12 months. If we do not obtain a favorable licensing agreement at that point, we plan to continue moving towards commercialization by developing the dedicated software and planning multi-center prospective studies. 03/01/2017 University of Louisville UofL - ExCITE image of external link icon Health IT Algorithms to severity of cardiac stenosis Cardiology Available Eric Castlen
A Biomimetic Human Platelet Bioreactor Jonathan Thon We are developing a microfluidic bioreactor that mimics human bone marrow to produce donor-independent human platelets from human induced pluripotent stem cells. We seek to first support and then replace the current donor based system. Platelets are the 'band-aids' of the bloodstream, responsible for clot formation and blood vessel repair. Platelet transfusions dramatically increase survival rates following cancer treatment, transplant and surgery, for which more than 2 million Americans receive life-saving platelet transfusions annually. Unfortunately, the demand for platelets exceeds supply and the available product is risky. The unmet market demand for platelets is $285 million/year (500,000 platelet units/year). Replacing the current donor-based system is a $1.7 billion/year opportunity. Our approach involves using biomimicry to reproduce the microenvironment where human platelets are made (i.e. the human bone marrow) in a microfluidic bioreactor, and trigger platelet production using the very same stimuli these cells experience in the body (i.e. shear, protein contacts, media composition). In our bioreactor, time to initiation of platelet production is reduced from 6 hours to immediately, the percent of platelet-producing progenitors is increased from 10% to more than 90%, and the time to completion of platelet production has been reduced from 18 hours to 2 hours (submitted, Thon et al. Science, 2014). Platelet morphology, ultrastructure and function of our bioreactor-derived platelets is comparable and consistent with donor platelets. We have filed a system and method patent for this technology and are currently generating IP for a second patent filing on a scaled bioreactor, which will be filed this year. This grant is aimed at validating the generation of donor-independent human platelets at scale using our patented biomimetic human platelet bioreactor. We expect that the findings made as a result of this investigation will provide proof-in-value of human bioreactor-derived platelets for technology licensing. 07/01/2014 Brigham and Women's Hospital BBIC image of external link icon Therapeutic Device Thrombocytopenia and other indications of platelet need Licensed Erin McKenna
A Blood Coagulation Sensor for Point of Care Use Seemantini Nadkarni We have developed a low-cost, multi-functional blood coagulation sensor that can measure a patients coagulation status within 5 minutes using a drop of blood. This device addresses the critical unmet need to identify and manage patients with an elevated risk of life-threatening bleeding or thrombosis, the major cause of in-hospital preventable death. In addition, our innovation will enable rapid coagulation testing in the doctors office or at home for over 15 million patients worldwide who routinely receive oral anticoagulants to prevent venous and arterial thrombosis, the worlds number one killer. Coagulation testing at the point of care is currently the fastest growing segment of the in vitro blood diagnostics market, with nearly $2 billion in global annual sales. Driven by the immediate need for improved blood product utilization and the rapidly growing numbers of patients receiving anti-coagulants worldwide, the coagulation testing industry is expected to burgeon by nearly 5-fold over the next decade. The blood coagulation sensor described in this proposal is well positioned to have a significant competitive advantage over other point of care coagulation devices. This is because current devices can only measure clotting time and often fail to identify the underlying coagulation defect. As a result, additional time-consuming laboratory tests are yet performed to assess relevant parameters: clotting rate, fibrinogen, fibrinolysis and platelet function, to reveal the underlying cause of bleeding or thrombosis. Mechanical devices such as thromboelastography (TEG) can quantify these parameters in real-time; however, given the high cost, large size, complex operation and requirement for cumbersome sample preparation, these devices are unsuitable for point of care use. Our proposed coagulation sensor uniquely combines the strengths of a low-cost, hand-held module with the capability to quantify multiple relevant coagulation parameters required to diagnose the underlying coagulation defect within a fraction of the time of laboratory tests and at ~2% of the cost of TEG. Our approach, termed optical thromboelastography (OTEG) involves placing a drop of blood (50?L) in a disposable cartridge. A laser source, similar to a common laser pointer illuminates the blood sample and a small camera images laser speckle patterns reflected from the sample over time. By analyzing laser speckle intensity fluctuations in real-time, we can measure the viscoelastic properties of blood during coagulation and recover information about multiple coagulation metrics in less than 5 minutes, with early results available within 1 minute.1-5 OTEGs capabilities for comprehensive coagulation profiling at the bedside will have major clinical impact in identifying patients at high risk of bleeding or thrombosis, tailoring blood transfusion and anti-coagulation protocols, and monitoring hemostasis during therapy to improve patient outcome. 08/01/2014 Massachusetts General Hospital BBIC image of external link icon Diagnostic Device Blood coagulation Available Erin McKenna
Development of an Implantable Intracardiac Soft Robotic Right Ventricular Ejection Device Nikolay Vasilyev Heart failure represents a significant public health concern. Most heart failure therapy aims at treating the left heart, however dysfunction of the right ventricle (RV), right heart failure (RHF), has received little attention until recently. For end-stage RHF, the most effective treatment is heart, lung or heart-lung transplantation. Mechanical circulatory support (MCS) to treat end-stage heart failure has become accepted as a therapeutic solution, when a donor organ is not available. Fundamentally however, currently available MCS devices are pumps that move blood through an artificial surface, bypassing or accelerating flow within the failed left and/or right heart, which requires permanent anticoagulation and is associated with bleeding/thromboembolic adverse events. To address this limitation as it pertains to RHF, we propose an implantable intracardiac device that is tailored specifically to augment blood ejection from the RV and requires much less anticoagulation. The device is based on soft robotic actuation and delivers a dynamic pulsatile force timed to the cardiac cycle, which effectively augments pumping function of a failed RV. The device is delivered via a minimal incision of the chest wall and then through a small opening into the pericardial space under image guidance, which significantly reduces invasiveness of the procedure. This project will focus on the two aims: Aim 1, we will design and assemble a prototype of the implantable intracardiac soft robotic right ventricular ejection device (RVED) and assess performance on a bench-top model and in an ex vivo tissue model of the RV. In Aim 2, we will couple the RVED to a controller and evaluate its performance in a large animal model. A key focus for the project is transition from a proof-of-concept prototype that addresses the scientific and technical feasibility to a fully functional device. A critical task of the project is development of the controller that would allow testing of the RVED in an animal model. Development of such a novel device and then bringing this technology to market will broaden circulatory support armamentarium for patients with end-stage RHF. 12/01/2014 Boston Children's Hospital BBIC image of external link icon Therapeutic Device Right ventricular heart failure - bridge to transplant Available Erin McKenna
Portable MR Device for the Pulmonary ICU Samuel Patz Our overall goal is to develop a portable, low field, magnetic resonance (MR) device that can be used in the Intensive Care Unit (ICU) at the bedside. The device will be used to measure regional changes in lung density in adults with Acute Respiratory Distress Syndrome (ARDS) as a function of ventilator pressure. It will be used to allow clinicians to set ventilator pressures that are safe for the patient. We call this device a MR-Lung Density Monitor (MR-LDM). The magnet is a low field (~0.01T) planar (or monohedral) magnet that creates a remote homogeneous field region surrounding a field saddle point located outside of its boundaries. The signal one detects is the average signal from this remote region, which is not an image. When positioned on the chest surface, the homogeneous field region is located entirely inside the lung parenchyma. Similar to using a stethoscope, a different region of the lung can be interrogated by moving the position of the magnet on the chest. The exact shape of the homogeneous field region is determined by the spatial field profile of the magnet whereas its size is primarily determined by the receiver detection bandwidth. Even at this very low field strength, good signal to noise ratio (SNR) results have been obtained from a lung volume of ~20cc in less than one minute. To date, our measurements of lung density have been obtained inside a RF shielded room. To deploy the MR-LDM at the bedside without interfering with medical care of the patient, an alternative way to attenuate environmental noise must be developed. In this proposal, our aim is to design, build and test an active noise cancellation (ANC) system for the MR-LDM that provides at least 40dB of external noise attenuation. 12/01/2014 Brigham and Women's Hospital BBIC image of external link icon Diagnostic Device This project is considered too early to have well defined clinical indications Available Erin McKenna
Developing a Biocompatible Elastic Sealant Ali Khademhosseini Damage to delicate soft tissue, such as lung tissue, is particularly challenging to repair. Lung tissue that has been punctured by biopsy or injury must be sealed surgically via sutures, staples, or the implantation of a surgical mesh. However, these operations are time- and skill-intensive, and many post-surgical complications can occur, including infection due to incomplete wound sealing, tissue damage and scarring. Sutures and staples also do not effectively repair other membranous or elastic tissues, including the dura mater, urethral and bladder tissue. In some patients, lung tissue is so fragile that surgeons prefer to use an adhesive sealant instead of or in addition to standard surgical closure methods. Although several tissue adhesives are commercially available, none are ideal surgical sealants for repairing delicate soft tissue. It is extremely challenging to achieve significant adhesion to soft tissues while minimizing tissue damage. Cyanoacrylate, for example, is strongly adhesive, but its degradation products can induce an intense inflammatory response and it is not approved for subcutaneous use. Fibrin glues, on the other hand, are more biocompatible, but they have low adhesive strength and poor cohesive properties. Additional limitations of commercial tissue sealants include: high cost, limited availability, and, in some cases, long curing times of the adhesive. Therefore, there is an unmet need for an inexpensive, biocompatible tissue sealant with strong adhesion strength and high elasticity to repair delicate soft tissue, such as lung tissue. We have recently developed a biocompatible and photocrosslinkable gelatin-based sealant, methacrylated gelatin (GelMA), which possesses higher adhesion strength to tissues than commercially available fibrin glues. Based on these properties and our preliminary data, we believe that GelMA is appropriate for delicate applications, such as the sealing of lung tissue. GelMA is comprised of modified natural extracellular matrix (ECM) components that can be crosslinked via UV exposure to create an elastic and biodegradable hydrogel. The mechanical properties of GelMA can be tuned for various applications by changing the methacrylation degree, GelMA concentration and UV exposure time. 03/01/2015 Brigham and Women's Hospital BBIC image of external link icon Therapeutic Device Lung sealant, surgical sealant indications/applications Available Erin McKenna
Intracardiac MRI Ablation-Monitoring Catheter Ehud Schmidt MRI is increasingly used diagnostically, either prior to or after cardiac electrophysiology (EP) Radio-Frequency Ablation (RFA) procedures, since it is uniquely able to detect scar, arising from infarction or ablation, as well edema and hemorrhage from acute injury.MRI can also provide cardiac vascular anatomy. As a result, use of MRI can improve (i) the targettting of existing pathology and (i) reduce arrhythmia recurrence after therapy (currently 30% for Atrial Fibrillation and 50% for Ventricular Tachycardia). Despite these capabilities, MRI is seldom used during EP therapeutic interventions, due to the lack of MRI-compatible interventional devices. Several companies are currently engaged in the construction of MRI-compatible EP RFA catheters, which will allow navigation, ECG measurements and ablation of the heart inside the MRI. There is little attention, however, to improving the speed of the MRI imaging process, which is currently very long (>1 hour), and forms a major barrier to clinical acceptance. Our BWH group of hardware physicists, electrical engineers and electrophysiologists, has constructed a number of EP devices that can be used both within and outside the MRI bore. With American Heart Association funding, we prototyped and tested a patented Intra-Cardiac MR Imaging (ICMRI) catheter, which has approximately 10 times the Signal-to-Noise-Ratio available with surface MRI coils, so it dramatically reduces imaging time. ICMRI is built on an expandable frame and mounted on a 4-mm diameter sheath, which is advanced together with the EP ablation catheter through the vasculature. When imaging is required, ICMRI is expanded, forming a 40-mm diameter forward-looking ("flash-light") MRI antenna, optimized for sensitive imaging of the RFA ablation region. ICMRI is also equipped with an array of tracking coils, insuring stability during imaging, preventing image artifacts due to physiological motion (breathing, heart contraction). We would like to complete a commercial version of ICMRI. We require funding to manufacture, test and verify in animal models its robust performance, so that this technology can be licensed and made available to the field. 05/01/2015 Brigham and Women's Hospital BBIC image of external link icon Diagnostic Device EP ablation procedures to be performed under MR Optioned Erin McKenna
Therapeutic Apheresis by Microfluidic Acoustic Separation Jason Fiering Therapeutic apheresis is a procedure used to remove specific blood components for the treatment of autoimmune and blood disorders. During apheresis, blood is removed from a patient, the pathologic blood component is discarded, and the healthy blood components are returned to the patient. The procedure is first-line therapy in several grave conditions including thrombotic thrombocytopenic purpura (TTP) and stroke in sickle cell disease. The technologic foundation of therapeutic apheresis has not changed in over 40 years. Thus, the application of apheresis has been restricted to what the available technology permits and is not driven by what patient care demands. Current apheresis platforms rely on bulky centrifuge technology, and as a result relatively large volumes of blood must be processed outside the patient. The impact of this large extracorporeal blood volume (ECV) must be managed to avoid cardiovascular instability, especially in pediatric patients. Clinicians are able to mitigate untoward effects of large ECVs, but the methods are not free from complications. Centrifugal apheresis is not suitable for low rate, continuous operation, thereby limiting its efficiency when serial procedures are needed. To enable groundbreaking new therapies, we propose a blood separation technology based on acoustics, in which cell types can be selectively channeled into distinct fractions with the application of ultrasound. Though the concept of blood separation with acoustics is not novel, we are the first to successfully adapt the technology for disposable plastic cartridges, where previous attempts used costly, specialized engineering materials. We combine this innovation with expertise in microfluidics to engineer a significantly lower-volume and higher-efficiency platform for apheresis. We anticipate that our technology will reduce ECV from the current minimum of 160-280 mL to a range of 10-60mL. This is a significant reduction considering that pediatric patients may have only a few hundred mL total blood volume. In addition, our technology will be scalable to adapt to any necessary flow rate and allow for continuous operation. To date we have demonstrated up to 99% separation efficiency using acoustics. We have separated plasma, red blood cells, white blood cells, and platelets, and we have established that hemolysis is negligible. With a DRIVE award, we will demonstrate the ability to achieve separation purity and yield comparable to that of existing centrifugal equipment and prove that acoustic separation can meet the performance requirements for therapeutic apheresis. These results will position us for follow-on commercial investment. Ultimately, we will expand the applications of therapeutic apheresis with the advantages of continuous operation and low flow rates achievable with our technology. 05/01/2015 Draper Laboratory BBIC image of external link icon Therapeutic Device Apheresis Available Erin McKenna
Confocal Microscopy for Intraoperative Discrimination of Cardiac Conduction Tissue Aditya Kaza Approximately 32,000 new cases of congenital heart defects occur in the US per year and there are ~1.5 million new cases worldwide. More than 20,000 congenital cardiac operations are performed each year in the US. Advances in diagnostic technologies, refinement of surgical techniques, and improvements in postoperative care have all contributed to favorable outcomes in this complex group of patients. However, there are several complications associated with surgical intervention including dysfunction of sino-atrial and atrio-ventricular conduction pathways. These complications require chronic cardiac rhythm management using implantable pacemakers. With more complex procedures, the risk of complete heart block or sinus node dysfunction increases accordingly (Table I). Lifetime costs and morbidity associated with pacemaker implantation in pediatric patients are very high. The economic burden of this rhythm management therapy is significant, especially when considering the average lifespan of these young patients. Despite the significant improvement in surgical results, there is still a critical barrier that needs to be overcome, which is to avoid preventable causes of conduction defects. This proposal aims to improve outcomes of surgical interventions by bringing recently developed microscopic imaging technology to the operating room. Using real-time and portable fiber-optics confocal microscopy (FCM) we have developed a systematic methodology for intraoperative identification of conduction tissue. Refinement and validation of this technology could potentially decrease the incidence of preventable causes of conduction delays in the operating room. Imaging technology including endoscopy, fluoroscopy, and ultrasound have allowed surgeons to probe deeper and less invasively into the most remote body locations. These imaging techniques; however, do not provide real-time microscopic information on tissue structure and function. In contrast, intraoperative microscopic imaging has the potential to assist heart surgeons by discriminating tissue types based on underlying structural and functional differences. Our preliminary studies over the past four years and peer-reviewed manuscript suggests that image data obtained with standard scanning confocal microscopy from fixed heart tissue preparations allows for discrimination between ventricular working myocardium, atrial working myocardium, sino-atrial node (SAN), and atrio-ventricular node (AVN) tissue. We will investigate if FCM using specialized microprobes (Figure 2) and fluorescent labeling techniques can provide clinicians with images of sufficient information to discriminate between these tissue types. 07/01/2015 Boston Children's Hospital BBIC image of external link icon Therapeutic Device Cardiac surgery imaging for identification of conduction tissue Available Erin McKenna
Impedance-Based, Continuous Hematocrit Monitoring in the Trauma Population Xin Zhang This proposal seeks to develop and validate an impedance-based approach to the continuous, real-time measurement of hematocrit in traumatically injured patients. Specifically, leveraging microelectromechanical systems (MEMS) technology, a conventional peripheral intravenous (IV) catheter will be enabled with an impedance-sensing capacity, thereby enabling the continuous, highly accurate monitoring of hematocrit in these patients. We envision that this advance in technology may enable the earlier detection of hemorrhage and a more timely surgical and/or blood transfusion management. 07/01/2015 Boston University BBIC image of external link icon Diagnostic Device Hematocrit measurement/diagnostic use in trauma and other potential surgical applications Available Erin McKenna
Variable Stiffness Microcatheter for Navigation of Tortuous Vessels Leo Tsai Endovascular procedures performed by interventional radiologists, cardiologists, neurologists, and vascular surgeons often require navigation across small tortuous vessels to access their target lesion. Microcatheters are required to deploy embolic agents, thrombolytics, medications, stents or retrieval devices, or diagnostic contrast agents. Navigation to the target is usually achieved with a combination of guidewires and microcatheter, and becomes difficult when the microcatheter encounters a sharp turn. The catheter must be flexible enough to round the corner, but stiff enough to allow it to cross the turn (known as “pushability”) once it has been made. Operators need to torque and repeatedly slide back/forth their catheter across sharp turns and may sometimes need to exchange for another device with a different stiffness if unsuccessful. This contributes to delays that add to material costs (e.g., OR time, additional devices) and clinical costs (e.g., delay in treatment, additional radiation exposure). Since microvessels are highly variable from patient to patient, procedure times for complex endovascular procedures are often highly unpredictable, which in turn reduces efficiency of the OR workflow. Current activelysteerable catheter designs cannot be practically scaled down to the microvascular (mm) scale. Operators currently rely solely on microcatheters with no active adjustment capabilities. 11/01/2015 Beth Israel Deaconess Medical Center BBIC image of external link icon Therapeutic Device Peripheral and neurovascular clinical indications: to access distal, tortuous vasculature and support controlled and selective infusion of diagnostic, embolic, or therapeutic materials into vessels Available Erin McKenna
Electric Nitric Oxide Generation for Medical Purposes Warren Zapol Inhaled nitric oxide (NO) was approved by the FDA in December, 1999 as a life saving therapy producing selective pulmonary vasodilation in neonates with persistent pulmonary hypertension of the newborn (PPHN). Inhaled NO has a remarkable safety profile with no major side effects reported after 25 years of clinical use in over 500,000 pediatric and adult patients. There is also limited but compelling evidence that many other patients, including those with chronic obstructive pulmonary disease (COPD – Vonbank et al., 2003), idiopathic pulmonary fibrosis (IPF – Blanco et al., 2011), chronic pulmonary arterial hypertension (PAH – Benza et al., 2015) and congestive heart failure (CHF – Semigran et al., 1994) might benefit from NO. However these patients are neither currently treated with NO nor systematically studied to demonstrate the potential benefits of breathing NO, because of NO’s high cost and lack of portability. Although NO is the standard of care for the treatment of PPHN, NO is only available for use in the US, EU and Japan, at a price of $5,000 (EU) - $14,000 (US) per baby treated. MGH spends approximately $900,000 per year for NO therapy, almost twice what is spent on O2. We believe patients need less expensive and easier access to inhaled NO. There is also a critical need for user-friendly, lightweight and portable inhaled NO to address chronic indications. We propose to develop and test a portable and affordable lightweight NO generator, building on our published benchtop device that uses pulsed electrical discharges to generate NO from air (Yu et al., 2015). We published bench and pre-clinical data showing that plasma generated NO is safe and functionally equivalent to tank-NO. This NO generator will expand the population of patients around the world who could benefit from NO inhalation therapy in-hospital by providing a cost-effective point-of-care solution and accelerate research into chronic indications. The innovative goal of this project is to optimize the plasma NO generator, which will produce NO from air that is purer than our current published prototype, while reducing production of potentially harmful byproducts, including NO2, O3 and electrode metal fragments. The proposed studies include identifying novel electrode materials and testing new designs for the spark generator. We propose to minimize the weight and size of the inline NO generator to permit placing the device within the inspiratory line of a newborn’s ventilator. In addition, we will reduce the power requirements of the NO generator, enabling portable applications with NO to be delivered through nasal cannulae or a mask. Power for the optimized NO generation device will be provided by batteries and will require only a miniaturized scavenging and HEPA gas filtration system. The portability, simplicity, and affordability of the optimized NO generator will benefit both in-hospital and ambulatory patients and will facilitate future studies identifying novel applications for portable NO inhalation therapy. 12/01/2015 Massachusetts General Hospital BBIC image of external link icon Therapeutic Device Neonates with persistent pulmonary hypertension (PPHN) adults with COPD, idiopathic pulmonary fibrosis, chronic pulmonary arterial hypertension Licensed Erin McKenna
MRI-compatible voltage device tracking for multimodality electrophysiology Ehud Schmidt Cardiac Electrophysiology (EP) treats cardiac arrhythmia. The major diseases are Atrial Fibrillation and Ventricular Tachycardia, which effect ~4 Million and 0.5 Million US patients, respectively. Catheter interventions are the most effective therapy. The interventions consist of; (A) diagnostic electro-anatomic mapping (EAM), mapping the location, size and geometry of electrical voltages on cardiac-chamber walls, detecting arrhythmia-conduction pathways, (B) pathway ablation using radio-frequency/cryogenic energy, and (C) post-ablative validation of arrhythmia termination. MRI is used at all stages of intervention. It is used (A) pre-operatively to assess anatomy and scar causing AF or VT, (B) intra-operatively to monitor ablation necrosis and edema, and (C) post-operatively to validate ablation success. However, EAM and ablation are still performed primarily in conventional EP labs, so multiple patient transfers to and from MRI are required (Multi-modality intervention). For efficient Multi-modality procedures, patient transfer and incorporation of multi-modality information must be easy. Voltage Device tracking (VDT) is used in >90% of EP sites, since VDT catheters collect both location and voltage data using electrodes placed on catheter shafts. We showed that VDT can be performed both inside and outside the MRI scanner without registration, using MRI-compatible VDT catheters that stay inside the patient, forming the only tracking method that allows efficient multi-modality intervention. The study develops a means for VDT tracking during MRI imaging, overcoming gradient-induced-voltage noise. It will allow accurate and fast incorporation of MRI data from all EP-procedure stages performed inside MRI. We will prototype a method based on a theoretically-based-technique developed for MRI-compatible 12-lead ECG. 05/01/2016 Brigham and Women's Hospital BBIC image of external link icon Diagnostic Device Atrial Fibrillation and Ventricular Tachycardia Available Erin McKenna
Rapid Perfusion Catheter Gabriel Gruionu Peripheral intravenous (PIV) catheter placement is difficult in critically ill patients throughout the hospital. Patients with hypotension require rapid infusion of fluid and blood products using a large diameter IV catheter (14G), but unfortunately their veins are constricted and only a smaller diameter catheter (22G) can be introduced easily. This limitation results in delayed delivery of fluids, longer recovery and poor patient outcomes. To address this, we have invented the Rapid Perfusion Catheter (RPC) that achieves a rapid and non-traumatic catheter diameter increase using the current needle insertion technique. We are filing a provisional patent. Preliminary animal and clinical experiments using FDA approved IV catheters revealed the approach is feasible but the existing devices do not fit in terms of diameter, length, and connectivity between components. The purpose of this study is to prove technical feasibility of a functional prototype. The prototype will be built by adapting existing angiocatheters. The animal testing will be performed in 10 farm pigs using a hypotension swine model in an ear vein to test the hypothesis that rapid transition from small to large catheters, and delivery of IV fluids are feasible without host vein damage. The clinical study and commercialization plan will be proposed to the next stages of funding. RPC is applicable to all PIV procedures - a market of 200 million devices in the USA alone. The regulatory pathway is most likely a class II 510(K) approval based on predicates such as the BD’s Angiocath Catheters and Cook’s Introducer Set devices. 05/01/2016 Massachusetts General Hospital BBIC image of external link icon Therapeutic Device Hypovolemic hypotensive shock Available Erin McKenna
Pharmacokinetics of Multifunctional Nanochelators in Iron Overload Disorders Jonghan Kim Increased iron stores are associated with well-established risk factors of heart and liver failure, arthritis, dyslipidemia and diabetes. Iron overload occurs in several anemias (e.g. thalassemia, sickle cell anemia, myelodysplastic syndrome, Diamond-Blackfan anemia) due to transfusion. In addition, hereditary hemochromatosis is a genetic iron overload disorder, affecting 7-32% of North American populations with genetic variants. Notably, several neurodegenerative diseases (e.g. Alzheimer’s and Parkinson’s diseases) are associated with high iron stores in the brain. Although chelation therapy has been widely used to improve disease conditions in patients with iron overload, iron chelators have serious adverse effects, including hypotension, tachycardia, agranulocytosis, neutropenia, neurotoxicity, musculoskeletal-joint pains, gastrointestinal disturbances and even death. Obviously, there is an urgent need to establish a new therapeutic strategy by improved chelators to treat tens of millions of people affected by iron overload disorders. The primary focus of our proposed project is to develop ultrasmall nanoprobes that covalently bind iron chelators (“nanochelators”) and thus limit drug distribution into non-target tissues, while efficiently capturing plasma iron and being exclusively cleared via urine, which decreases iron burden and reduces the risk of iron-induced tissue damage, including heart diseases and dyslipidemia. The specific aims of this study are 1) to develop ultrasmall, renally-clearable nanochelators to effectively harvest iron and 2) to characterize the therapeutic efficacy of nanochelators in a rat model of hemoglobinopathy. By addressing these questions, we hope to both identify novel therapeutic approaches and improve clinical outcomes. 08/01/2016 Northeastern University BBIC image of external link icon Small Molecule Drug Iron overload disorders Available Erin McKenna
A Manganese Alternative To Gadolinium for MRI Contrast Eric Gale Gadolinium based contrast agents (GBCAs) are routinely administered to visualize vascular and tissue irregularities using MRI. Unfortunately, concerns over GBCA toxicity in patients suffering kidney disease have emerged over the last decade. In 2007 the FDA labeled all GBCAs with a black box warning and current American College of Radiology guidelines advise against using GBCAs in patients suffering moderate-to-advanced chronic kidney disease (CKD), acute kidney injury, or requiring dialysis. GBCA sales dropped by 1 million vials (~10%) in the year following the FDA issued warnings. This decrease reflects contrast withheld from patients suffering moderate-to-advanced CKD 8% of the US population. No replacement technology has emerged and CKD patients are continuously denied contrast enhanced examinations. We developed a non-gadolinium containing contrast agent to be compatible with renally insufficient patients. Our product operates analogously to the standard of care but with an improved toxicity and clearance profile. The primary indication for our product will be MR angiography, but it is amenable to any applications requiring GBCAs. CKD patients provide an immediate market penetration point for our product but we also expect to compete with GBCAs in patients with healthy kidney function. The goal of this B-BIC DRIVE grant is to de-risk our product for clinical development through the following milestones: 1) demonstrate equivalence to GBCA in imaging myocardial viability in a mouse model; 2) demonstrate equivalence to GBCA in MR angiography in a NHP model; 3) quantify DMPK in rats and NHPs; 4) evaluate acute and sub-acute dose toxicity in rats. 09/01/2016 Massachusetts General Hospital BBIC image of external link icon Diagnostic Device Use in medical imaging Optioned Erin McKenna
Minimally Invasive Tissue Engineering Therapies for Acute Airway Injury Elazer Edelman Airway inhalation injury is a significant health risk producing severe lung damage and respiratory failure, and is the most common cause of death in burn centers. Despite advances in burn therapy, treatment of inhalation injury remains disappointing. A lack of specific treatments for inhalation injury combined with a narrow intervention window illustrates the dire need for targeted therapeutic approaches. By embedding healthy bronchial epithelial and endothelial cells within porous matrices, we created stable cell constructs which can be easily implanted into peri-tracheal soft tissue surrounding injury sites. The matrix micro-environment allows for cell preservation with significant shelf-life, ready transport, and an effective therapeutic unit with no demonstrable immune response. These tissue engineered cell constructs demonstrate quantifiable biosecretory function from the moment of insertion both in vitro as well as on bronchial injury in small animals. We have also generated a cellularized gelatin particle formulation which can be deployed as an injectable, expandable gel around sites of injury. Given promising preliminary findings from implantable formulation large animal pilot studies, we propose to expand investigation of this technology to full large animal trials and additionally to begin large animal pilot studies on injectable formulations once this technology is optimized. Ultimately we envision two minimally invasive clinical formulations in treating inhalation injuries; an implantable cellularized matrix and injectable matrix particles in an expandable gel. The latter can be injected around the site of injury by first responders while the former can be deployed at designated medical centers as definitive therapy for inhalation injury. 10/01/2016 Massachusetts Institute of Technology BBIC image of external link icon Therapeutic Device Airway inhalation injury Available Erin McKenna
A Prototype Laser Device for Treatment of Thrombocytopenia Mei Wu Thrombocytopenia is a major hematological disorder in association with an increasing risk of hemorrhage and death. Current therapeutic alternatives under development include using growth factors to stimulate megakaryopoiesis, but all these agents enhance the growth of hematopoietic stem cells (HSCs) and megakaryocyte progenitors in a fashion independent of circulating platelet counts. In sharp contrast, we describe here a simple, cost-effective, noninvasive means to increase platelet regeneration in vivo in a drug-free and donor-independent manner by stimulating megakaryocytes with near-infrared light. The light treatment can directly increase a rate of platelet generation from each megakaryocyte without affecting natural regulation of the number of megakaryocytes by platelet counts so that thrombosis can be effectively prevented. We have demonstrated that the low level laser at a specific setting could stimulate mitochondrial biogenesis and increase the rate of platelet production from megakaryocytes, greatly mitigating induced thrombocytopenia in two mouse models. We propose to fabricate a prototype laser device that can stimulate platelet regeneration in larger animals like pigs. If successful, the likelihood of this device to work in humans is very high because the depth of spinal cord, a major site of platelet generation in adults, beneath the skin is similar between these two species. The technology represents a ground-breaking strategy for management of thrombocytopenia. It can also serve as effective alternatives for primary or secondary prophylaxis of thrombocytopenia and for reducing the need of platelet transfusions. 11/01/2016 Massachusetts General Hospital BBIC image of external link icon Therapeutic Device Thrombocytopenia Available Erin McKenna
Accurate Sepsis Diagnostic Using a Neutrophil Microfluidic Device Daniel Irimia Sepsis affects more than 1 million Americans each year, has 30% mortality rate, and for the past five years the incidence of sepsis has increased 13% per year. Sepsis treatment demands the resources of an intensive care unit (ICU) and consumes 7% of Medicare budget (~$50 billions/year). However, despite sepsis being an expensive and growing problem, our current abilities to diagnose sepsis remain imprecise (70% accuracy). The limited accuracy of current diagnostic abilities has two crucial consequences. Patients that are septic and do not receive prompt treatment in an ICU setting have high mortality rate. Patients who are not septic but are treated in ICUs until the diagnostic of sepsis is ruled out, consume ~25% of the resources for treating sepsis (~12 billions/year). An assay that enables the diagnostic of sepsis early and with high accuracy could save lives and free substantial resources. We have recently designed and tested a microfluidic assay for sepsis diagnostic that relies of precision measurements of patient neutrophil motility phenotype from one droplet of blood. Preliminary validation of the assay in 24 patients in trauma ICU at MGH showed that the assay performs at 98% accuracy, with 0% false negative results. The assay can predict which patient will develop sepsis, 2-3 days in advance, with 85% accuracy. The goal of this pilot proposal is to extend the validation of the assay on a larger number of patients in the trauma, medical ICU and the emergency department at MGH. 03/01/2017 Massachusetts General Hospital BBIC image of external link icon Diagnostic Device Sepsis Available Erin McKenna
SQPAN Michael Sweeney The field of the invention is systems and methods for cardiac electrical stimulation and electrocardiographic monitoring for autonomous device-based diagnostic and therapeutic decision-making. A method for a fully implantable, subcutaneous, powered, wireless, personal area network (PAN), or “body bus”, for long-term, ambulatory, electrocardiographic surveillance using an array of physically independent but cooperating sensors, coupled with implanted devices that provide timed electrical stimulation, or pacing, to generate improvement in cardiac structure and function, is provided. Such electrical therapy systems may include multiple stimulation electrodes at various locations within and outside the cardiac surface in various combinations. The exemplary implementation addresses the controlled initiation and propagation of single or multiple opposing radial wavefronts generated by pacemaker stimulation and fused with spontaneous cardiac electrical activity to normalize electromechanical activation in heart failure, termed “cardiac resynchronization therapy (CRT)”. The sum of these electrical waves is expressed as the body surface QRS complex, which is characterized and quantified using a novel method of wave interference superposition between 2 or more point sources (‘fusion”). The autonomous, body-worn SQ PAN technology solution integrates near- and far-field human cardiac electrical wave recordings with computational firmware for subcutaneous electrocardiographic recording and analysis for QRS complex-based fusion titration during CRT. The subcutaneous short range wireless network uses low-power integrated circuits and physiologic signals to achieve a wireless body-worn electrocardiographic sensor network. The implanted sensors collect various physiological signals designated for therapy titration and clinical event prediction. The physically separate devices can automatically and quickly associate, or “pair” electronically. 05/01/2017 Brigham and Women's Hospital BBIC image of external link icon Therapeutic Device Heart failure Available Erin McKenna
Development of an electroceutical for treatment of comorbidity between hypertension and major depression Jill Goldstein Hypertension is a leading cause of morbidity and mortality in the United States with an overall prevalence of approximately 29%, corresponding to 70 million of Americans. Despite the benefits of existing blood pressure lowering drugs, 50% of hypertensive patients are inadequately controlled while taking medication and reduction in cardiovascular disease (CVD) incidence remains an important goal. A chronic withdrawal of vagal tone has been involved in treatment-resistance, structural cardiac remodeling and progression to CVD in hypertensive subjects, suggesting this marker as a potential novel therapeutic target. Hypertension is also frequently associated with major depression, with an estimated comorbidity of 22%. Patients with hypertension and comorbid depression are particularly prone to present cardiac vagal dysregulation, and have an increased risk for the development of CVD. Furthermore, this particular group of patients represents a challenge to physicians and healthcare providers who are unable to reach blood pressure target reductions with available antihypertensive medications, and need to consider cardiac adverse events and complicated cardiovascular prognosis with the use of some antidepressants. Hypertensive patients, and in particular those with comorbid depression, could greatly benefit from an intervention oriented to regulate vagal activity, with subsequent effects in blood pressure and cardiovascular risk reduction. Given preliminary work from our group, we are proposing the development and validation of an enhanced transcutaneous vagus nerve stimulation system by gating the stimulation to specific variations in respiratory and cardiac activity, which will optimize its effects in blood pressure reduction and cardiovascular autonomic modulation in hypertensive patients with comorbid depression. 06/01/2017 Brigham and Women's Hospital BBIC image of external link icon Therapeutic Device Hypertension Available Erin McKenna
Molecular Imaging of Dysregulated Angiogenesis in Pulmonary Arterial Hypertension Paul B. Yu Pulmonary arterial hypertension (PAH) is a disorder of elevated pulmonary vascular resistance characterized by progressive remodeling and obliteration of resistance-determining vessels of the pulmonary circulation. Despite current therapies, transplant-free survival following the diagnosis of PAH remains slightly better than 50% at 5 years, due primarily to right heart failure. Outcomes in PH could be improved with earlier diagnosis, and with deployment of therapies that directly target pulmonary vascular remodeling before irreversible changes have occurred. Here we describe a pre-clinical development program for a positron emission tomography (PET) molecular imaging diagnostic test for PAH. This strategy utilizes a radioisotope-conjugated (89-Zr) humanized monoclonal antibody directed against VEGF (bevacizumab) to detect abnormal angiogenic activity in the pulmonary vessels of individuals in the early stages of pulmonary vascular disease. The rationale is based on histopathologic evidence of disordered angiogenic activity in the affected vessels of human disease, and molecular and histologic data from animal models of PAH demonstrating dysregulated angiogenic signaling. Our molecular probe is retained avidly in remodeled small pulmonary arterioles and vascular lesions in a robust animal model of PAH, and binds avidly to vascular lesions in sectioned human lung tissues affected by PAH. This pre-clinical development program would advance the first molecular imaging agent specifically designed for the diagnosis and management of pulmonary vascular disease, and provide a technology which would enable non-invasive identification of disease at earlier stages to permit earlier intervention, and could help to identify treatments which have the ability to modify the natural history of disease. 06/01/2017 Brigham and Women's Hospital BBIC image of external link icon Diagnostic Device Pulmonary arterial hypertension Available Erin McKenna
A Novel Coaxial Deflectable Microcatheter for Rapid Navigation of Tortuous Vessels Leo Tsai We have developed a microcatheter using a patent-protected novel coaxial design that allows active deflection of the microcatheter tip in both directions, while satisfying size requirements for general microvascular and neurovascular procedures and preserving the tracking and torqueing properties of conventional microcatheters. This obviates the need to stock or use different-shaped microcatheters, wires, or guide catheters. Other catheter deflection technologies cannot be configured to the required scale and length. Our design also lowers production costs to allow price-matching to competing high-end passive microcatheters. Our target users are general and neuro-interventional radiologists. The potential market size is $225M world-wide with rapid growth driven by advances in minimally-invasive therapies. We demonstrated proof of concept in a vascular testbed under a B-BIC Pilot grant, and more recently demonstrated superiority against predicate devices in a live animal model. Our specific aims are to achieve key elements in design verification, validation, and testing as part of an overall goal towards 510k approval. We intend to achieve 510k approval in two years and first in-human use. 08/21/2017 Beth Israel Deaconess Medical Center BBIC image of external link icon Therapeutic Device Peripheral and neurovascular clinical indications: to access distal, tortuous vasculature and support controlled and selective infusion of diagnostic, embolic, or therapeutic materials into vessels Available Erin McKenna
Inhibition of abnormal airway smooth muscle contraction by inhbitors of the α5β1 integrin Dean Sheppard and William F. DeGrado Asthma is common disease that affects ~ 5% of the population of most industrialized countries and is responsible for substantial morbidity. Currently available therapies are most effective in patients with mild disease, but only ~ 50% of patients with severe disease respond to available therapies, a group estimated to include more than 2 million people in the US and EU. Exaggerated airway narrowing, caused by contraction of airway smooth muscle, is a central feature in all patients with asthma, so better therapies targeting smooth muscle contraction are a large unmet medical need. Most efforts to prevent or reverse airway smooth muscle contraction have targeted the core contractile pathway that leads to increased phosphorylation of smooth muscle myosin and resultant actin-myosin contraction. We recently identified a parallel pathway that is required for maximal force generation – tethering of airway smooth muscle cells to extracellular fibronectin, that is mediated by a single integrin, a5b1. This tethering is not required for normal maintenance of smooth muscle tone, but appears to be critical for the exaggerated airway smooth muscle force generation induced in models of allergic asthma and after incubation of murine tracheal rings or human bronchial rings with the asthmagenic cytokines IL-13 and IL-17. We have found that a small molecule inhibitor that is highly specific for the a5b1 inhibits exaggerated airway narrowing and force generation in vitro and that delivery of even a very low affinity inhibitor directly into the airways inhibits allergen-induced airway hyperresponsiveness in vivo. Drugs targeting a5b1 have progressed to phase 2 clinical trials for inhibiting angiogenesis in cancer without limiting toxicity. However, as anticancer agents, they have not been optimized for high selectivity and convenience of dosing required of an agent for treatment of this chronic illness. The purpose of the current proposal is to develop an a5b1 inhibitor in novel IP space that is optimized for oral or aerosol delivery. Such a drug holds great promise to meet the unmet medical need of treating airway narrowing and disability in patients with severe asthma who are refractory to current therapies. 08/01/2016 UCSF UC-CAI image of external link icon Small Molecule Drug Small molecule drug targetting asthma Asthma Available Gemma Rooney
SpheraHance, a cancer-targeted contrast agent for MRI and CT imaging Mohammad Tariq Malik Magnetic resonance imaging (MRI) and computed tomography (CT) are used frequently to detect, rule out, and monitor almost all types of cancer. Injectable contrast agents are frequently used to highlight suspicious masses, but these often cannot distinguish malignant from benign growths, and cannot detect small lesions. The product proposed in this application is a cancer-targeted contrast agent that should have improved specificity for malignant vs. benign lesions and improved sensitivity that could ultimately be useful for early detection of cancer, particularly lung cancer. The product consists of gold nanoparticles (for CT contrast) coated with gadolinium (MRI contrast) and a cancer-targeting aptamer that causes particles to concentrate inside malignant cells. To reach the market, this technology will first need to show an acceptable toxicity profile and improved contrast compared to current standards in animal models, and then would need to go through clinical trials to achieve FDA approval. This project will first identify optimal particles, test them in vitro and in cells, proof-of-concept in vivo studies (biodistribution and contrast properties in nude mice with lung cancer xenografts), toxicity and biodistribution in rats, and in vivo studies in a transgenic mouse model of lung cancer. The team consists of faculty members from the Departments of Medicine and Bioengineering with expertise in cancer drug development, nanomaterials, and imaging. 02/01/2016 University of Louisville UofL - ExCITE image of external link icon Combination Nanotechnology contrast agent Lung Cancer Available Holly Clark
Development of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKPB4) inhibitors for the treatment of cancer Sucheta Telang Because of increased anabolic and energetic requirements, most cancer cells need to accelerate the glycolytic pathway. This appears to occur through increased activity of phosphofructokinase 1 (PFK-1). This is enabled by production of fructose-2,6-bisphosphate (F26BP) produced by a family of four enzymes termed 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB1-4). For one of these, PFKFB3, an inhibitor has been developed (PFP158) and is now in phase I clinical trials. The PI has evidence that a second family member, PFKFB4, is equally critical in supporting the growth and metabolism of NSCLC cells. This proposal intends to further modify the lead PFKFB4 inhibitor, 5MPN, and carry out in vitro and in vivo tests of its anticancer activities ultimate goal of obtaining a successful clinical candidate PFKFB4 inhibitor to decrease the glycolytic flux, survival and growth of tumors in NSCLC patients. The investigators outline the following milestones: 1) Synthesis of lead compounds followed by testing of inhibition in NSCLC cell lines; 2) Synthesis of second generation compounds; 3) Synthesis of third generation compounds; 4) Selection of 10 compounds based on physical properties; 5) In vitro ADME and drug inhibition screening; 6) Pharmacokinetics will be examined of intravenous and oral administration of selected 5MPN derivatives in female mice. 7) In vivo safety and efficacy of two 5MPN derivatives 8) In vitro combination studies of two candidate compounds with other chemotherapies; 9) In vivo combination studies with other chemotherapies. The go/no go points for each milestone are: If the inhibitors examined at #1,2,3 are not effective, they will go back a step to choose other candidates. If #4 or #5 do not yield viable candidates, they will go back and examine others. At the end of the 2 years, the goal is to obtain an effective and potent pre-clinical candidate compound with an excellent pharmacokinetic and safety profile, then use this compound for further development towards IND-enabling studies towards the conduct of a Phase I clinical trial. The PI's laboratory was responsible for the examination of the kinase activity of PFKFB4 in NSCLC and the effects of decreasing PFKFB4 expression in vitro and in vivo and is highly experienced in biological assays to evaluate effects of inhibition of PFKFB4 expression. She developed the first PFKFB4 inhibitor, 5MPN, in collaboration with other members on this team, who also developed the initial PFKFB3 inhibitors, which formed the basis for the clinical candidate, PFK158. Additionally, a medicinal chemist has been added to the team who will direct those components of the project. 02/01/2016 University of Louisville UofL - ExCITE image of external link icon Small Molecule Drug PFKPB4 inhibitor Lung Cancer Available Holly Clark
Defining a next-generation local anesthetic agent Jeffrey C. Petruska Local anesthetics are drugs which stop the conduction of electrical signals along the nerves/axons of the peripheral nervous system. The major purpose of local anesthetics is to prevent pain?producing signals from reaching the spinal cord and brain to enable surgical procedures and as treatment options for many difficult pain conditions. Although widely?used, existing local anesthetics are all derived from cocaine and have significant limitations such as toxicity and side?effects. One major side?effect is loss of motor ability, because they also block conduction of signals from the nervous system out to muscles. Based on data from rat experiments, our product stops pain like existing local anesthetics but is novel in that it has lesser effects on the motor system and may have reduced toxicity. We believe this because it is not structurally?related to cocaine, is already FDA?approved for veterinary use where it has been used successfully in many species for decades for other purposes, and has had successful Phase 1 clinical trials in human. The local anesthetic actions of our drug are novel and protectable and are not part of the existing uses or IP for the drug. GOAL: To determine if our drug is an FDA?approvable local anesthetic agent for use in humans. We propose to generate data to make specific determinations required to reach a major inflection point along the path toward commercialization. The first milestones will be to determine if our drug is capable of exerting local anesthetic effects using cultured human sensory neurons (this is NOT a clinical trial) and if the dose?response is within acceptable limits of drug concentration. If these are successful we will then use cultured human cardiac tissue to determine the therapeutic window of our drug compared to existing local anesthetics. These major milestones are required to ensure maximal potential for successful progression toward clinical utility. We also propose to determine if our drug uses the expected basic mechanisms for local anesthetics, a determination required for FDA?approval. Additional work will determine if the local anesthetic actions are achieved through mechanisms other than those known for our drug (this could significantly strengthen our IP), and will determine the degree of spared motor function (this could strengthen IP and marketability). Expected outcome: If our drug is an FDA?approvable local anesthetic agent, the proposed work will greatly enhance licensing opportunities and/or enable pre?clinical testing. The team consists of scientists, clinicians, and contractors who are experts with pain mechanisms, pain treatment, and drug development for pain indications. 03/01/2016 University of Louisville UofL - ExCITE image of external link icon Small Molecule Drug New use of Atipamezole Cornea Licensed Holly Clark
Development of a mutated human parvovirus B19 vaccine Alfred B. Jenson Human parvovirus B19 (B19) is a small DNA virus that infects rapidly dividing red blood cell (RBC) precursors, and is highly contagious. In healthy children, B19 infection causes unpleasant but rarely serious symptoms including fever, headache, and a “slapped cheek” rash that spreads to the trunk and extremities. However in children or adults, who have hereditary and acquired anemias, B19 is a very common cause of life-threatening aplastic crisis. Of these anemias, the largest single group in the US is comprised of those with sickle cell disease (SCD, >100,000 in US) and hereditary spherocytosis (HS, >60,000in USA) is the second largest group. A significant proportion (36 - 86%) of aplastic crises in sickle cell anemia patients are attributed to B19 infections. These B19-associated life-threatening events could be almost completely prevented if a B19 parvovirus vaccine were available. There has been substantial interest from industry in developing such a vaccine, but two human clinical trials with conventional B19 vaccines consisting of viruslike particles (VLPs) were discontinued because of adverse side effects and low immunogenicity. We have now identified the likely cause for these side effects and have developed a novel approach with mutated VLPs, that will avoid any adverse effects but will increase immunogenicity, thereby enabling development of a safe, efficacious B19 vaccine. We are requesting EXCITE funds to produce the mutated VLPs and to test their immunogenicity and side effects in the only animal model that is suitable for B19 testing: the macaque monkey (rodents are not susceptible to B19 infection). If successful, we envision that the B19 vaccine would be given to high-risk populations (SCD and HS patients) during infancy to help prevent aplastic crisis. The use of the vaccine could eventually be expanded to the general population because B19 (like other viruses such as rubella and zika), though generally benign, can cause fetal death or defects, if a woman is infected during the first or second trimester of pregnancy, particularly during epidemics. In our previous work, we used a similar approach to develop the human papillomavirus (HPV) VLPs that eventually led to the cervical cancer vaccines, Gardasil and Cervarix, so we are confident in our ability to move this project to the next level. 08/01/2016 University of Louisville UofL - ExCITE image of external link icon Vaccine Human parvovirus B19 vaccine Human parvovirus B19 Available Holly Clark
Adenosine deaminase as a novel immunotherapeutic agent for the treatment of cancer Kavitha Yaddanapudi Cancer immunotherapy using immune checkpoint inhibitors (ICIs) to target molecules that prevent the immune system from attacking cancer cells (e.g. anti-PD-1, anti-CTLA-4 antibodies) has revolutionized the treatment of metastatic melanoma, resulting in long-term complete responses for many patients. Still, there remains an urgent need for new strategies because not all patients respond to ICIs and resistance can occur in those that do. The purine nucleoside, adenosine, is produced in copious amounts within the tumor microenvironment, where it serves to suppress the immune system and promote tumor growth. There is evidence to suggest that overproduction of adenosine can mediate resistance to ICIs. We propose to develop a cancer immunotherapy involving intratumoral administration of adenosine deaminase (ADA)—an enzyme that irreversibly converts adenosine into inosine, a non-immunosuppresive nucleoside. A pegylated version of bovine ADA (PEG-ADA), made by Sigma Tau Pharmaceuticals, is already FDA-approved for use as an enzyme replacement therapy in children with ADA-associated severe combined immunodeficiency (ADA-SCID), a rare genetic disease caused by mutations in ADA. Our preliminary studies show that administration of PEG-ADA to immunocompetent mice with malignant melanoma is effective at inhibiting tumor growth and modulates the tumor microenvironment by depleting immunosuppressive T regulatory cells while boosting immune cells that promote tumor rejection. For this ExCITE project, we propose to perform additional preclinical studies in mice in order to determine the optimal dose/ schedule for PEG-ADA treatment and to confirm that PEG-ADA is synergistic with ICI treatment. In Year 2, we propose to perform a human Phase I/II clinical trial of PEG-ADA in combination with an ICI (Pembrolizumab) in patients who have inoperable stage IIIB to IVM1c malignant melanoma. The PEG-ADA required for these studies will be provided by Sigma-Tau. Upon successful completion of the ExCITE project, the technology would have proven clinical feasibility as a cancer immunotherapy that could be used as a monotherapy or in combination with ICIs and we envision that a company such as Sigma-Tau would then license our recently filed patent related to using PEG-ADA as a cancer immunotherapy. Although the initial indication for PEG-ADA would likely be unresectable malignant melanoma, it is potentially useful in many additional cancers types (e.g. non-small cell lung cancer, renal cell carcinoma, bladder cancer, and prostate cancer). There are many companies focused on developing cancer immunotherapies, but none appear to be pursuing this innovative approach. Moreover, depleting adenosine is expected to be highly synergistic with both existing and emerging immunotherapeutic strategies. Furthermore, the regulatory pathway for our technology is well established because we are repurposing an existing drug, making it likely that PEG-ADA could be approved for use in melanoma and other cancers in a fraction of the time needed for a new molecular entity. 08/01/2016 University of Louisville UofL - ExCITE image of external link icon Biologic Drug Pegylated bovine adenosine deaminase Melanoma Available Holly Clark
Exosome miRNAs as diagnostic tools of melanoma Hongying Hao Accurate diagnostics remain a major challenge for melanoma. Traditional pathology alone is not a true gold standard to identify borderline lesions that range from dysplastic nevus (non-malignant lesions) to invasive melanoma. More than necessary, aggressive treatment is often recommended for non-malignant lesions, which results in net harm to patients. Furthermore, no reliable and convenient modalities exist for diagnosing recurrence after surgical resection of melanoma. Frequently, expensive imaging tests are ordered to monitor recurrence, but often with substantial rates of false-positive results. An inaccurate diagnosis of recurrence can lead to more unnecessary medical expenses for the patient. Our solution is to introduce a dynamic, minimally invasive exosome technology to diagnose melanoma and detect recurrence. Exosomes are organelle-like vesicles released into body fluids from tumor cells. Exosomes have functional microRNAs (exoRNAs) mirroring the tumor cells and with considerable value for mapping tumorigenesis and progression. We propose using a unique exoRNA signature in serum exosomes to dynamically monitor the disease status of an individual patient over time. We have a United States patent titled Characterizing Melanoma (patent No. 9,493,840, issued on November 15, 2016). The issued patent provides methods of diagnosing and characterizing melanoma by measuring exoRNA species in a patient sample. We have shown that 6 specific exoRNA species relate to melanoma; thus, their detection in a sample can lead to accurate detection of melanoma. We propose three parallel milestones. Milestone 1: Standardize protocols for biospecimen processing and exosome isolation to meet NIH and FDA requirements. Milestone 2: Maximize the performance of the 6- exoRNA panel, including evaluating analytical sensitivity and specificity to ensure that our test is rigorous, reproducible, reliable, and convenient for clinical laboratories. Milestone 3: Validate the 6-exoRNA panel for detecting recurrence of melanoma using patient samples in our biorepository. An experienced biostatistician will be included in Milestones 2 and 3. Our technology has several advantages: (1) sensitive and specific for early diagnosis, (2) low-risk and minimally invasive for convenient use, (3) dynamic for frequent monitoring of disease status, (4) a much higher value of care than other diagnostic modalities, and (5) compatible with other diagnostic approaches. Our goal is to use the ExCITE funds to develop our product from a research-focused assay to a laboratory test that meets the requirements of CLIA (Clinical Laboratory Improvement Amendments) based on our patented biomarkers. This should advance the product to the point where we can apply for NIH SBIR funding to complete pre-clinical studies and provide the foundation for clinical trials to obtain FDA approval. This teams broad expertise in basic science, clinical practice and clinical translation, coupled with a desire to learn more about research commercialization, will ensure a high chance of success for this project. 08/01/2017 University of Louisville UofL - ExCITE image of external link icon Diagnostic Device exoRNA-based diagnostic test Melanoma Available Holly Clark
NANOFIBER TISSUE ENGINEERED VASCULAR GRAFT USING 3D PRINTING TECHNOLOGY Narutoshi Hibino, MD (Transferred to Christopher Breuer, MD after Hibino moved to new institution) Researchers at Nationwide Childrens Hospital and Medical Center are developing novel nanofiber-based, patient-specific tissue-engineered vascular grafts that overcome many of the limitations that exist with current graft technology. Coronary and peripheral vascular bypass graft procedures are performed in approximately 600,000 patients annually in the USA with a market size anticipated to exceed $3.5 billion by 2022. While there are several synthetic and biologic graft products available, problems remain with the need to manually fashion each graft to fit the specific patient, biocompatibility, infection, and the ability of the graft to accommodate patient growth. Using 3D printing, the team has developed a novel method to create patient-specific, biodegradable, tissue-engineered vascular grafts (TEVG). Preclinical studies have demonstrated that once a TEVG is implanted, it begins to encourage new cellular growth with the long term goal of the graft being completely replaced by the patients own tissue. Such a biodegradable graft offers major advantages compared to current mechanical and tissue engineered products. 08/01/2014 NATIONWIDE CHILDREN'S HOSPITAL NCAI-CC image of external link icon Medical Device Vascular Grafts Optioned Mark Low
Custom Patient-Specific Airway Stents Thomas R. Gildea, MD Approximately 5,000 airways stents are placed each year in the U.S. with a potential of 150,000 patients per year worldwide. Currently available airway stents, also known as tracheobronchial prostheses, are wrought with complications, disadvantages, and inefficiencies in addressing the airway disease market. The sizing and simple tube shape of available “off-the-shelf” stents, even when extensively modified for a patient’s anatomy, rarely fit in place as delivered. Furthermore, due to these initial sizing and fit issues, stents are frequently changed or modified, requiring multiple interventions every few weeks or months to manage the complications of poor fit, migration, obstruction, and/or infection. Dr. Gildea’s team has developed a solution to address the major challenges facing airway stenting. Patient-specific stents, designed utilizing a CT scan of the patient’s airway and custom software to prescribe the size, shape, and angles of any branching of the stent, may mitigate stent migration, granulation tissue surrounding the stent, and perhaps reduce risk of infection. Patient-specific stents may also reduce operating time by eliminating the need for intraoperative modification of standard stents to match patient anatomy and extend the useful life of the stent. Dr. Gildea’s team has developed a software product to enable quick turnaround time to 3D print a customized stent designed to fit the patient’s own anatomy and disease state. 03/01/2015 Cleveland Clinic NCAI-CC image of external link icon Medical Device Airway Stenting Optioned Mark Low
Neuromodulatory Implant Device for the Treatment of Obstructive Sleep Apnea Frank Papay, MD Cleveland Clinic researchers have developed a fundamentally different approach to treat Obstructive Sleep Apnea (OSA) via neurostimulation. According to industry estimates, an estimated 18 million Americans suffer from OSA with over $7.4 billion spent annually on diagnosis and treatment of the condition, and expenditures growing at a rate of 13% per year. Current approaches to treatment, primarily through continuous positive airway pressure (CPAP), are expensive, inconvenient, uncomfortable, and subject to inconsistent use. Although several companies are developing neurostimulatory devices for OSA, the solutions are limited by traditional neurostimulation device configurations involving an implantable pulse generator (IPG) placed in a subcutaneous surgical pocket below the clavicle and surgically placed leads, similar to cardiac pacemakers and spinal cord stimulators for chronic pain. Such surgical pockets and leads are the leading source of device-related complications, notably infections. The Cleveland Clinic team has developed an implantable transmandibular externally rechargeable device to stimulate specific isolated anterior glossal (tongue) muscles innervated by the branches of the hypoglossal motor nerve. Once stimulated, these anterior tongue muscles will pull the posterior tongue base forward, thereby relieving airway obstruction. The product features a miniaturized, externally-powered, integrated lead design the permits less invasive implantation and eliminates the risk and cost of infections related to the surgical IPG implantation. The approach carries the potential to be better tolerated than current OSA therapies, to improve patient compliance, and to result in better outcomes. 08/15/2015 Cleveland Clinic NCAI-CC image of external link icon Medical Device Sleep Apnea Licensed Mark Low
Augmented Visualization for Minimally Invasive Cardiovascular Surgery: AugMed3D Eric Roselli, MD Minimally invasive cardiothoracic surgery (MICS) has been shown to have many benefits for patient care, such as smaller scars, less pain, shorter hospital stay after surgery, lower risk of infection and bleeding, shorter recovery time, and faster return to normal activities. However, the smaller surgical exposure leads to inherently decreased anatomical visibility for the surgeon, which presents difficulty in navigating to and operating within the field of interest, and results in adding time to the procedure. Dr. Roselli and colleagues at Cleveland Clinic are developing a new visualization system that enables Augmented Reality (AR) guidance during minimally invasive cardiovascular surgery, with aortic valve repair as the first targeted application. The project is directed towards development of a software-based Augmented Reality 3D visualization system, AugMed3D, which will register and combine direct visualization of the surgical field with a semitransparent 3D digital model obtained via preoperative radiological imaging, and displayed through optical see-through eyewear devices. The benefit will be improved intraoperative visualization to enhance anatomic localization and navigation resulting in decreased learning curve, operative complexity, and procedure time, and improved healthcare economics. 02/01/2016 Cleveland Clinic NCAI-CC image of external link icon Medical Device Minimally Invasive Cardiothoracic Surgery Available Mark Low
Technology for Diagnosis of Cystic Fibrosis in Two-Week-Old Newborns Miklos Gratzl, PhD Researchers at CWRU have developed a diagnostic device that permits diagnosis of cystic fibrosis (CF) within the first few weeks after birth. CF is the second most common life-threating autosomal recessive disorder with a prevalence of 1 in 2300 live births in the US. The current gold standard for CF diagnosis is a chlorine sweat test; however, newborns typically are not able to produce enough sweat for diagnosis until the age of 3 months or greater. Within those first few months, irreversible damage may have already occurred, mainly to the pancreas, intestines, and most importantly, lungs. The CWRU team has developed a diagnostic device that allows accurate CF diagnosis using significantly less sweat than needed for current chlorine sweat tests. The technology being developed requires only 2 microliters of sweat, which can be obtained from babies as young as 2-week-old. This tiny volume of sweat is sampled with very high accuracy and the measurement itself is absolute. Therefore calibration of the analytical unit is not required. No special expertise is needed and the diagnostic test will be inexpensive. This novel CF diagnostic will make it possible to begin treatment shortly after birth which will help reduce later morbidity due to pulmonary, gastrointestinal, cognitive and other complications, leading to extended life expectancy. 02/01/2016 Case Western Reserve University NCAI-CC image of external link icon Diagnostic Cystic Fibrosis Available Mark Low
Novel Therapeutics for Difficult-to-Treat Breast Cancer Venkatram Mereddy, PhD To develop drug candidates that inhibit tumor glycolysis while limiting toxic side effects to normal cells. 01/01/2016 University of Minnesota MN-REACH image of external link icon Small Molecule Drug novel monocarboxylate transporter inhibitor – nitric oxide donor (MCT1/4-NO) hybrid derivatives Breast Cancer Available Kevin Anderson
Instrumented urethral catheter for distributed pressure and EMG measurements Rajesh Rajamani, PhD To produce a robust and well-tested prototype instrumented catheter that simultaneously measures both bladder and urethra function, enabling differentiation between structural and neural problems and evaluation during clinically relevant provocative maneuvers 04/01/2016 University of Minnesota MN-REACH image of external link icon Diagnostic Device urethral catheter for distributed pressure and EMG measurements Urinary incontinence Available Kevin Anderson
Targeted Cardio-Cerebral Extracorporeal Membrane Oxygenator (TC-ECMO) Arthur Erdman, PhD An external oxygenation device to provide bloodflow to the heart and brain of a cardiac arrest patient until the patient could be transferred to a larger medical center. This device would be easy to use by a trained health professional and decrease mortality associated with cardiac arrest. 10/01/2016 University of Minnesota MN-REACH image of external link icon Therapeutic Device Extracorporeal Membrane Oxygenator Cardiac arrest Available Kevin Anderson
WristBot: A robotic system for the diagnosis and physical rehabilitation of sensory and motor dysfunction of the wrist and hand Juergan Konczak, PhD This device is designed to provide objective diagnostics and physical rehabilitation treatments for various wrist/hand dysfunctions resulting from neurological diseases. The device will provide an automated, yet patient-specific rehabilitation treatment. 10/01/2016 University of Minnesota MN-REACH image of external link icon Diagnostic Device, Therapeutic Device A robotic system for the diagnosis and physical rehabilitation of sensory and motor dysfunction of the wrist and hand Neurological and orthopedic disease affecting hand/wrist motor function Available Kevin Anderson
Brain Enhanced Hearing Aid: Combining Somatosensory Neuromodulation with Sound Stimulation to Treat Tinnitus Hubert Lim, PhD A device that combines nerve and sound stimulation in the ear to treat tinnitus. This device will have advantages over some current treatments due to the fact that it is non-invasive and cost-effective. 10/01/2016 University of Minnesota MN-REACH image of external link icon Therapeutic Device Neuromodulation device Tinnitus Available Kevin Anderson
Novel methods for reversing dental caries in human enamel Alex Fok, PhD The proposed product provides non-invasive methods for reversing dental carious lesions (cavities). Two distinct products are proposed: one suitable for repairing tooth erosion and tooth wear; and, one suitable for repairing sub-surface and white spot lesions. 03/01/2017 University of Minnesota MN-REACH image of external link icon Small Molecule Drug Remineralization therapy Caries Available Kevin Anderson
SnoreX: A fun, science based app to reduce snoring Conrad Iber, MD This project will develop a fun and simple mobile health application to reduce apnea events in patients with obstructive sleep apnea. Patients will use their own voice to control a series of games and these vocalizations will improve the patients' airway muscle endurance to decrease apneic events. 03/01/2017 University of Minnesota MN-REACH image of external link icon Combination (Diagnostic Device, Therapeutic Device) smartphone application that uses engaging voice-controlled games to build muscle coordination and endurance of the upper airway Obstructive Sleep Apnea Licensed Kevin Anderson
An imaging device to unveil, non-invasively, information linked to microscopic anatomical structures in human tissues for clinical diagnosis Pierre-Francoise Van de Moortele This device will enable standard MRI equipment to be upgraded for further investigation of the cerebral cortex at higher resolution, enabling investigation of inter-neuronal microscopic fiber pathways critically involved in both normal and pathological conditions. 10/01/2016 University of Minnesota MN-REACH image of external link icon Diagnostic Device Add-on device to MRI scanners for high-resolution imaging Neurology Available Kevin Nickels
IND enabling experiments for Intracellular Sigma Peptide in Acute Myocardial Ischemia Isabelle Deschenes Developing a novel therapeutic for enhancing sympathetic nerve regeneration for prevention of Sudden Cardiac Death in patients with AMI and ischemic heart disease. 08/01/2017 Case Western Reserve University NCAI-CC image of external link icon Therapeutic Myocardial Infarction Available Mark Low
Micro Gas Chromatography and Breathomics for Acute Point-of-Care Diagnostics in Acute Lung Injury Xudong Fan Development of a portable, fully automated, high-performance multi-dimensional micro-gas chromatography device, which can be attached to a mechanical ventilator to rapidly and continuously detect exhaled volatile organic compunds relevant to Acute Respiratory Distress Syndrome. 08/01/2017 University of Michigan NCAI-CC image of external link icon Diagnostic/System Acute Lung Injury Available Mark Low
Development of a small molecule for treatment of immune thrombocytopenia (ITP) Michael Holinstat Development of a small molecule which functions to inhibit platelet activation while causing only limited bleeding, and which has been shown to not only prevent systemic thrombosis, but specifically immune-mediated thrombosis of the lungs, a common pathology observed in ITP. 08/01/2017 University of Michigan NCAI-CC image of external link icon Therapeutic Thrombocytopenia Available Mark Low
Cell X Device Validation for iPS Clone Selection and Cardiomyocyte Fabrication George Muschler Development of a reproducible automated method of assessment, documentation, selection and manipulation for the generation of induced pluripotent stem cell-derived cardiomyocytes (CMs). 08/01/2017 Cleveland Clinic Foundation NCAI-CC image of external link icon Tool/Other Cell-based Myocardial Therapy Available Mark Low
Arterial Thrombolysis by VWF Aptamer: Optimizing Dose and Evaluating Toxicity in Mice Shahid Nimjee Development of VWF aptamer to provide an improved ischemic stroke treatment that is safe, effective, expands the window of pharmacological stroke therapy, minimizes the incidence of vessel re-occlusion, and provides thrombotic prevention during endovascular interventions. 08/01/2017 Ohio State University NCAI-CC image of external link icon Therapeutic Ischemic Stroke, Myocardial Infarction Available Mark Low
Developing Antibody-targeted nanoparticle-drug conjugates as a non-surgical treatment for AAAs Anand Ramamurthi Development of novel multifunctional doxycycline (anti-proteolytic drug) delivery via biodegradable polymer nanoparticles (NPs) for non-surgical therapy for abdominal aortic aneurysm. 08/01/2017 Cleveland Clinic Foundation NCAI-CC image of external link icon Therapeutic Aortic Aneurysm Available Mark Low
Motion-Activated System (MAS) to prevent chest tube clogging Kiyotaka Fukamachi, MD, Ph.D. Chest tubes are extensively used to drain blood after every cardiothoracic surgery procedure until bleeding stops. About 2.7 million cardiothoracic surgeries are performed in the United States each year, with two chest tubes used per case on average. Chest-tube complications are serious clinical and economic burdens. Patients with clogged tubes must undergo additional open-chest procedures, raising the average cost of care 55% (over $20,000 vs. non-complicated surgery). In cases of blood drainage-related complications, length of stay is prolonged by ~5 days versus 1 to 2 days for standard in-patient hospitalization. Dr. Fukamachi and team have developed a novel, disposable motion activated system (MAS) that can be attached to the outside of a chest tube to prevent clot build-up and associated obstruction of chest tubes with minimal supervision/interaction required of caregivers and to improve patients recovery, outcomes, and hospitalization costs. 03/01/2015 Cleveland Clinic NCAI-CC image of external link icon Medical Device Thoracic Surgery Available Mark Low
LTS: Lung Texture Score Selnur Erdal, MS, Ph.D. Pulmonary function testing is currently the standard tool for objectively assessing lung disease severity in chronic parenchymal and alveolar lung diseases, such as pulmonary sarcoidosis. However, pulmonary function tests are subject to variability, e.g. patient effort, technical laboratory methodology, different interpretive algorithms. High-resolution chest CT imaging is very sensitive for detecting lung pathology. However, current approaches to CT scan results interpretation are poorly standardized, requiring time-consuming volumetric tracing in identifying pathological features, which results in difficulty in evaluating interstitial lung disease (ILD). At present, there is no convenient, well-standardized, radiologist-generated CT image analysis approach that provides a reliable quantitative assessment of lung disease. Dr. Erdal and colleagues are developing a software tool that is an efficient, objective, and quantifiable approach to chest CT image analysis using an OSU published and peer-reviewed Lung Texture Score scale. The solution can be integrated into conventional workflows of commercial CT imaging systems or as a post-imaging workstation. 05/01/2015 Ohio State University NCAI-CC image of external link icon Diagnostic Tool Lung Imaging Available Mark Low
High Resolution IVUS Aaron Fleischman, PhD We propose to demonstrate a low-cost high resolution high frequency broad bandwidth (HFBB) ultrasonic transducer for IVUS (intravascular ultrasound). IVUS is a catheter based diagnostic system for tomographic intravascular imaging of coronary and peripheral vasculature. It is used to plan interventions, characterize plaque morphology,evaluate stent placement, and monitor progression and regression of plaques. 01/01/2017 Cleveland Clinic, Department of Biomedical Engineering NCAI-CC image of external link icon Diagnostic Intravascular Imaging Available Mark Low
ReProx Large Bore Vascular Closure Device Shengqiang Gao, Ph.D. The proposed NCAI project will fund the design and development for a minimally invasive applicator tool for a novel large-bore vascular closure technology developed by Cleveland Clinic and Lubrizol Corporation. The ReProx vascular closure system is patent-pending and uniquely positioned to capitalize on the large, and growing, market for tools that facilitate peripheral cardiac interventions that rely upon large-bore interventions like transcatheter aortic valve replacement. Successful completion of this project will result in a fully realized proof of concept system. 01/01/2017 Cleveland Clinic, Department of Biomedical Engineering NCAI-CC image of external link icon Device Vascular closure device Available Mark Low
Hyaluronan Enhanced and Biomechanically Designed Trans-catheter Aortic Valve Prosthesis Lakshmi Prasad Dasi, PhD While trans-catheter aortic valves (TAVs) bring valve replacement therapy to a larger patient population, the fact that they utilize fixed tissue as leaflets render them less durable and not cost effective from the standpoint of manufacturing, quality control, and storage. There is a strong need for a durable TAV that does not require anti-coagulant therapy to address the age old drawbacks plaguing all artificial heart valves to date. We have developed a potentially disruptive TAV technology that utilizes advanced biomolecule enhanced polymers and biomechanical design principles that has so far demonstrated strength, anti-thrombogenic, and anti-calcific properties. In this project, we will translate our innovative technology towards commercialization through clinical quality device manufacturing, controlled bench studies, and animal trials. 01/12/2017 The Ohio State University, Department of Biomedical Engineering NCAI-CC image of external link icon Device Percutaneous heart valve replacement Available Mark Low
The application of vortex airflow to continuous positive airway pressure (CPAP) therapy Liran Oren, PhD This proposal seeks funding from the NCAI for developing application of vortex airflow for the management of obstructive sleep apnea therapy 03/15/2017 University of Cincinnati, Department of Otolaryngology NCAI-CC image of external link icon Device Obstructive Sleep Apnea Available Mark Low
Smart Catheter for Target Mapping of Atrial Fibrillation Jayakumar Sahadevan We propose to develop a diagnostic mapping catheter to aid in the ablative treatment of atrial fibrillation (AF) with the capability of locating sources of AF for targeted ablation. The proposed device is a âsmart catheterâ comprised of two components, a novel mapping catheter and an analysis algorithm. This project will fund the fabrication and evaluation assessment of a 24 electrode catheter having the unique design of a 2-D matrix sheet of bipolar pairs in a fixed distribution to be used in conjunction with the algorithm which has been validated in patients with AF. The design of the mapping catheter and development of the algorithm is driven by our research data confirming the existence of AF sources in patients. 08/01/2017 Case Western Reserve University NCAI-CC image of external link icon Diagnostic device Atrial Fibrillation Available Mark Low
Developing biomarker based predictive algorithms for lung disease progression in CF Assem Ziady Development and validation of a series of novel serum protein biomarkers of cystic fibrosis that can be tested via proprietary algorithms to predict lung function decline by as much as 6 months in advance. 08/01/2017 Cincinnati Children's Hospital Medical Center NCAI-CC image of external link icon Diagnostic/System Cystic Fibrosis Available Mark Low
A new standard of care for imlant bed preparation utilzing an innovative drill bit technology Marcus Abboud The objective is to develop a new surgical drill bit that is capable of replacing the current standard of clinical implant bed preparations and surgical bone drilling. The new predicted standard allows for a dramatically shortened and more precise implant protocol, leading to a significant reduction in bone necrosis, enhanced early bone apposition, and ultimately immediate functional loading (IFL) capability of implants. The specific aim is to design a drill bit as a multi-diameter bit for a one-stage implant site preparation, instead of using a sequence of 4 drill bits in average with increasing diameters. This manifests a faster rate of penetration, lower surface and down hole torque, lower down hole vibrations, reduced material wear, higher efficiency and higher stability in all directions. Medical applications include implant, orthopedic and neurosurgeries. The North American market supports this new drill bit technology due to the shift toward one-stage procedures (OSP). Manufacturers have released more one-stage dental implant fixtures designed for IFL than ever before. Based on increased OSP’s, IFL protocols will grow at a strong compound annual growth rate (CAGR) of more than 15% in North America until 2016 (Millennium Research Report – US market for dental implants). 12/20/2015 Stony Brook University LIBH image of external link icon Therapeutic Device Other Available Peter Donnelly
Targeting pathogenic viral infections with first-in-class viral budding inhibitors Carol Carter This application proposes to assess a new paradigm for treatment of viral infections that circumvents many of the current issues limiting effective management. We propose to target a cellular factor that is critical for release of the virus from infected cells rather than the current practice of targeting viral-encoded products, which leads in every case to rapid emergence of resistant variants. We have identified such a factor and, over the past decade, its critical role in replication of a broad range of viruses has been validated. Now, using a small molecule we have found to bind our target and structural data defining target interaction with the compound, we propose to (i) assess the ability of the molecule to inhibit virus replication in human cells in culture; (ii) define the event in replication that is disrupted; and (iii) concomitantly use the agent as a lead compound to model, synthesize, and test new compounds, in collaboration with the Stony Brook University Institute of Chemical Biology and Drug Discovery. As this is a new strategy, the compounds we identify will define novel, “first-in-class” virus inhibitors. 12/20/2015 Stony Brook University LIBH image of external link icon Small Molecule Drug Virus inhibitor Viral infections Available Peter Donnelly
Orthovoltage -ray minibeams: brain tumor therapy with tissue-sparing incident beams F. Avraham Dilmanian Current radiation therapy methods of brain tumors produce neurocognitive deficits; the causes include large integral brain dose and damage to the cortex and temporal lobes. Orthovoltage X-ray Minibeams (OXM) segment the incident beams into arrays of parallel, thin (0.3 mm) planar beams (minibeams), which are known to spare tissues from synchrotron x-ray studies. As minibeams penetrate tissues they gradually broaden to merge with their neighbors, producing a solid beam at the proximal side of the tumor. Our studies of the method’s physical feasibility suggest that OXM spares the cortex and temporal lobes and reduces integral brain dose. We will use an existing 100-kVp orthovoltage machine together with our prototype multi-slit collimator to compare OXM and broad beams in a) their tolerance by the rat brain as measured by cognitive testing, micro-MRI, and tissue histology, and b) their efficacy to ablate the rat brain tumor 9L gliosarcoma with smaller impact on the brain. In a possible second year we could apply OXM to spontaneous brain tumors in domestic dogs by collaborating with veterinary hospitals and by using a 320-kVp machine. The proposed studies should strengthen our patent and allow us to obtain outside grants to reach early-stage human studies and commercialization. 12/20/2015 Stony Brook University LIBH image of external link icon Therapeutic Device Orthovoltage X-ray minibeams Brain tumors Licensed Peter Donnelly
Development of small molecule inhibitors for PLD6 as therapeutics for triple negative breast cancer Michael Frohman The Frohman lab cloned and has been studying the mammalian Phospholipase D signaling enzymes for two decades, including characterizing a PLD1&2 small molecule inhibitor with potential therapeutic utility in cancer. PLD6, which we also reported, is newly being associated as a driver in triple-negative breast cancer (TNBC) through promotion of cancer stem cell renewal, creating an imperative to develop a PLD6 small molecule inhibitor. Given the successful PLD1&2 inhibitors (which do not inhibit PLD6), PLD6 should be considered a highly-druggable target since it has a related catalytic site. We have conducted an in silico screen of FDA-approved and drug-like libraries, identifying compounds with hypothetical high affinity for the PLD6 catalytic site, all of which are commercially available. A PLD6 activity biochemical assay exists based on hydrolysis of a radioactively-labeled target followed by size separation on polyacrylamide gels and imaging. The project aims are to develop and use a high-throughput fluorescent PLD6 activity assay to test the in silico candidates for inhibition, to optimize the lead candidates and validate them using cellular assays, and as needed, to conduct screens of compound libraries to identify additional lead candidates. A PLD6 inhibitor would have broad utility and commercial potential for the cancer field. 12/20/2015 Stony Brook University LIBH image of external link icon Small molecule drug Develop a small molecule inhibitor for PLD6 as a cancer therapeutic Triple negative breast cancer Available Peter Donnelly
NEW-HARP: A highly sensitive avalanche selenium detector for time-of-flight (TOF) positron emission tomography (PET) Amirhossein Goldan The signal to noise ratio (SNR) of positron emission tomography (PET) can be substantially improved by time-of-flight (TOF) readout technique. The ultimate TOF detector is one with time resolution ?t < 10 picosecond (ps). Such a detector has still not been realized. Existing commercial systems utilize bulky and expensive photomultiplier tubes (PMTs) which are based on the complicated planoconcave photocathode and yet can only achieve ?t ∼ 500 ps. Silicon (Si) photomultipliers (SiPMs) are rapidly developing and have achieved better ?t than PMTs (i.e., SiPM ?t ∼ 100 ps). However, they suffer from poor photon detection efficiency, optical crosstalk, small area, poor uniformity, and high cost. The main goal of this proposal is to fabricate and characterize a novel avalanche picosecond detector that consists of (1) a sub-strate with nano-pattern multi-well electrode structure and (2) amorphous selenium (a-Se) photoconductive layer with avalanche multiplication. We call this detector NEW-HARP: Nano-Electrode multi-Well High-gain Avalanche Rushing Photodetector. The key advantages of NEW-HARP are uniform scalability over large area at substantially lower cost compared to crystalline solids, ∼90% detection efficiency in the blue wavelength, and compatibility with complementary metal-oxide semiconductor (CMOS) technology. These unique benefits of the NEW-HARP detector has made it an attractive candidate for commercialization by companies such as SynchroPET (Stonybrook, NY). 12/20/2015 Stony Brook University LIBH image of external link icon Other, Medical imaging Picosecond detector Diagnostic imaging Available Peter Donnelly
Novel miR-129 based therapeutics for colon cancer Jingfang Ju Colorectal cancer is the third leading cause of cancer mortality in both men and women in the United States. Resistance to chemotherapy is one of the major reasons for the failure of treating advanced colorectal cancer. Mounting evidence has demonstrated that non-coding microRNAs (miRNAs) are crucial regulators of gene expression, in particular, under acute genotoxic stress. Our recent studies discovered a novel mechanism of miR-129 mediated apoptosis by suppressing the expression of anti-apoptotic protein Bcl2, the 5-fluorouracil (5-FU) target protein thymidylate synthase (TS) and cell cycle control gene E2F3. We demonstrated that the loss of miR-129 expression in colorectal cancer patients is a critical event during disease progression. More importantly, we were able to reverse the chemoresistance in colon cancer stem cells with miR-129. In the proposed project, we will determine the therapeutic efficacy of miR-129 mimics in colon cancer model system. In Specific Aim 1, we will determine and optimize the therapeutic efficacy of miR-129 mimics in colon tumor xenografts. Specific Aim 2, we will conduct pharmacokinetics of miR-129 mimics in vivo. 12/20/2015 Stony Brook University LIBH image of external link icon Biologic drug miR-129 Colon cancer Available Peter Donnelly
Fast hybrid approach for determination of structure of therapeutic protein complexes Dima Kosakov Therapeutic proteins, including antibodies, affibodies and other scaffolds have become promising drugs for treating cancer, infectious and cardiovascular diseases, inflammation and immune disorders. Whereas the standard method for development of high-affinity therapeutic proteins uses combinatorial libraries in various display platforms, recent studies demonstrate the power of rational design approaches that utilize computational docking methods to predict 3D structure of the complex between therapeutic proteins and their targets as a starting point for the next round of optimization. However, these studies also show that current methods need improvements. One of the promising strategies can be a combination of computational docking with low resolution data obtained from chemical crosslink experiments. While these methods taken separately have achieved some scientific maturity, their combined use and commercialization is prevented by the fact that both methods are resource demanding and require highly skilled specialists. Here we propose to check feasibility of addressing those deficiencies, by 1) development of novel ultrafast protein docking algorithm able to deal with crosslinking restraints using regular desktop, 2) improvement of the crosslink protocol to simplify identification of crosslink sites. If successful it will enable us to create hybrid computational/experimental approach for protein complex structure determination, with significant market potential. 12/20/2015 Stony Brook University LIBH image of external link icon Other (research tool) Algorithm for predicting atomic resolution structure of complexes between therapeutic proteins and their targets. Protein complexes Available Peter Donnelly
Enhancement of protein yields using mechanical signals: augmenting biotech production to reduce drug costs Gabriel Pagnotti Bioprocessing techniques have profoundly advanced biopharmaceutical efficacy and availability for novel drug development and regenerative medicine applications, generating a multi-billion dollar industry. The resources necessary to distill cellular products which ultimately address heavy market demands, however, are costly and the processes, cumbersome, presenting a significant manufacturing bottleneck. Chemical and media-derived solutions can hinder persistence of cellular output preventing adequate yield in a burgeoning market. Predicated on established translational research demonstrating that low intensity vibrations (LIV), a sub-gravitational (<1g-acceleration), high-frequency (1-100Hz) mechanical signal stimulates cellular activity, this application proposes the use of low intensity mechanical signals as a novel strategy to overcome these limitations. Our objectives in performing these aims are to increase rate of proliferation and production of GFP, monoclonal antibodies, and recombinant-insulin in mesenchymal stem cells, hybridomas, and bacteria cells, respectively, by optimizing signal and temporal parameters to administer LIV. Our commercialization strategy will expand the range of LIV technology towards new in vitro applications, generating a foundation for future development of viable devices or for incorporation into existing incubation facilities. Intellectual property will be developed around these optimized parameters, incorporating refractory periods between administrations in order to improve titer and protein yield on an industrial scale. 12/20/2015 Stony Brook University LIBH image of external link icon Other (Class I Medical Device) A device that emits low intensity vibration in bioprocessing to increase cell proliferation Bioprocessing Available Peter Donnelly
Non-invasive acoustic radiation force therapy for osteoarthritis induced pain and cartilage regeneration Yi-Xian Qin This project’s long-term objective is to provide a safe non-invasive ultrasound medical device for the treatment of Osteoarthritis (OA). OA represents a significant burden to the health care system and affects the quality of life millions of people. Present treatments provide pain relief but no cure for the mechanism of action, cartilage deterioration. The market potential for a non-invasive and non-pharmacological device that provides cartilage regeneration is greater than $4 billion. The specific aim for this proposal is to determine the parameters needed for an ultrasound stimulator for optimum regeneration of cartilage. The parameters of the ultrasound stimulator, which include the signal frequency, energy level, waveform, and time of treatment, play a role in stimulating cell response, cellular signal transmission, and transfer of nutrients and oxygen to the cells. In order to determine the precise parameters needed, an ultrasound stimulator designed for bone regeneration must be reprogrammed with a variety of different parameters selected for cartilage regeneration; cellular and animal testing must be performed using the selected parameters; and the results of the testing must be analyzed to determine which of the selected parameters most optimally induces robust formations of cartilage while mitigating cartilage decay. 12/20/2015 Stony Brook University LIBH image of external link icon Therapeutic Device Non-invasive ultrasound medical device Osteoarthritis Available Peter Donnelly
Azasteroids for Combination anti-TB therapy Nicole Sampson One third of the world’s population carries the infectious agent that causes tuberculosis (TB), and every 21 seconds someone dies of TB worldwide. Using a privileged pharmacophore, our long-term goal is to develop a more effective drug-sensitive and drug-resistant TB combination therapy. The proposed therapy will reduce time of treatment, and consequently reduce treatment costs and improve treatment outcomes. We have identified a drug scaffold which has high host in vivo stability, low host toxicity, and excellent host bioavailability to develop as an anti-TB therapeutic and which is protected by a use patent. The specific aims in this proposal are to 1) improve the potency of lead compounds; 2) to analyze and if necessary, improve the mycobacterial metabolic stability of the most effective lead compounds from aim 1; and 3) to determine the host pharmacokinetic profile for the top lead compounds. The targeted outcomes for the end of the granting period are a) to be positioned to transition 3 top lead candidates of low toxicity and excellent ADME profile from in vitro to in vivo testing; and b) to improve the IP position of the products prior to commercialization. 12/20/2015 Stony Brook University LIBH image of external link icon Small molecule drug Pharmaceutical Tuberculosis Available Peter Donnelly
A novel glioblastoma drug - oncolytic virus PV1-Mono-Cre Eckard Wimmer Glioblastma multiforme (GBM) is one of the most deadly cancers with a median survival of 15 months despite of traditional surgery, radiotherapy and chemotherapy treatment. The only approved drug that is relative effective in extending the survival expectancy is temozolomide. However, the drug does not improve the overall survival rate, which remains less than 10% in 3 years. Therefore, a novel glioblastoma drug is urgently needed. Recently, the success in using the oncolytic recombinant poliovirus PVS-RIPO to treat glioblastoma patients, a procedure which was designed in our laboratory in Stony Brook, has prompted us to develop our novel recombinant virus design PV1-Mono-Cre in GBM model as well. PV1-Mono-Cre was highly effective as an oncolytic agent against neuroblastoma in both tissue cultures and transgenic mice model, while surpassing PV-RIPO in many aspects (PV-RIPO grows very poorly in neuroblastoma cells). Our goal in this project is to extend PV1-Mono-Cre's oncolytic spectrum to GBM, which has a much greater market needs. Our specific aims including: first, test the PV1-Mono-Cre in glioblastoma cell lines. Second, construct GBM mice models. Third, test the oncolytic effects of PV1-Mono-Cre in the GBM mice system. As a novel GBM drug candidate, our PV1-Mono-Cre could profoundly impact the current GMB drug market. 12/20/2015 Stony Brook University LIBH image of external link icon Biologic Drug PV1-Mono-Cre Glioblastma multiforme cancer Optioned Peter Donnelly
LDL as biomarker for childhood tuberculosis Xinxin Yang Childhood tuberculosis (TB) is estimated to contribute 10-15% of the disease burden in high-burden settings, with an estimation of about a million cases occurred in 2010 worldwide. Young children have a high risk of developing active disease and a propensity to develop severe and disseminated forms of disease following exposure to Mycobacterium tuberculosis (MTB). Existing diagnostic tools fail to confirm TB in the majority of children, who typically have paucibacillary disease. More sensitive and child-friendly diagnostic tools are urgently needed to diagnose TB in children. We have identified changes in serum lipoprotein that occur as a result of exposure to MTB. We refer to this modified lipoprotein as MtLDL. MtLDL induces conversion of activated macrophages into foamy macrophages. Thus detection of MtLDL in serum will serve as an indication of disease progression. Our hypothesis is that MtLDL will be detectable ex vivo and will serve as a diagnostic for disease progression. Two aims will be undertaken. Aim 1: We will prepare antibody that specifically cross reacts with MtLDL but not native LDL. Aim 2: We will analyze P1041 serum samples to demonstrate MtLDL presence in serum of TB patients. The data acquired in these experiments will provide the foundation for filing invention a provisional patent application for the diagnostic assay. Our long term goal is the development of a minimally invasive, robust, serum-based diagnostic tool to detect active tuberculosis in children. 12/20/2015 Stony Brook University LIBH image of external link icon Diagnostic Device Diagnostic marker of TB infection and disease status in children Tuberculosis Available Peter Donnelly
Therapeutic for Clostridium difficile antibiotic-associated diarrheal disease James Bliska This research will develop a novel therapeutic for Clostridium difficile antibiotic-associated diarrheal disease. C. difficile is the leading cause of nosocomial antibiotic-associated diarrhea worldwide. Patient treatment costs for this disease in the USA alone exceed $1 billion per year. Because current treatment strategies for this disease are failing, new therapeutic strategies are urgently needed. Secreted C. difficile toxins ToxA and ToxB bind to and enter into cells in the intestine and trigger pathogenic effects, resulting in mucosal inflammation and damage (Fig. 1). We have identified a protein that, when introduced into cells, terminates C. difficile toxin-induced pathogenesis. We will engineer this protein to contain receptor binding and cell entry functions, giving it the same cellular specificity as a C. difficile toxin. Upon entering into cells, either before or after they are intoxicated by ToxA or ToxB, this therapeutic will terminate pathogenesis, leading to protection of C. difficile-infected patients from mucosal inflammation and damage. An interdisciplinary co-PI team with expertise in microbial pathogenesis, immunology and bacterial toxins will produce a biologically active therapeutic and demonstrate its protective activity using pre-clinical in vitro and in vivo assays. 05/15/2016 Stony Brook University LIBH image of external link icon Biologic Drug A recombinant YOPM protein for treatment of C. diff infection C. difficile diarrheal disease Available Peter Donnelly
Device for rapid, simple and highly parallel single-cell processing Eric Brouzes Single-cell genomics is a set of methods that seek to obtain genomic information (copy number variant profile, genomic DNA, transcriptome, epigenetic state) of single-cells using quantitative PCR or sequencing. These methods are essential to extract genomic information from individual cells out of a complex mixture of cells, particularly in neurology, cell biology, immunology and cancer research. The impact of single-cell genomics has been recognized by the community and was named Method of the Year 2013 by Nature. The applications of single-cell genomics are mostly concentrated on the analysis of very rare cells such as unculturable bacteria, embryos and circulating tumor cells, and on the analysis of heterogeneous tissues such as tumors. Single-cell genomics already permitted to reveal unexpected mosaicism in the brain and to trace the clonal evolution of tumors. Despite its tremendous potential, single-cell genomics is hindered by a laborious workflow that has historically been manual and low throughput. In addition, the required number of cells to analyze can also be difficult to attain with existing methods. One of the key drivers of the growth of the single-cell genomics market is the development of innovative platforms to streamline the sample preparation of single-cells at high throughput. Our project proposes to develop a simple and effective method to perform molecular reactions at single-cell resolution. In contrast to existing methods, our approach 1) is simple to implement, 2) is directly compatible with existing workflows for sample preparation, thus 3) enables new analyses at single-cell resolution such as epigenetics; and 4) permits the analysis of a very large number of single-cells at once. In addition, our method will enable the concurrent analysis of genomic and spatial information within a tissue thus providing not only the genetic make-up of individual cells but also information about their micro-environment. One very exciting aspect of our approach is the vast array of applications that can be readily developed based on the core method, which makes our platform highly versatile: single-cell qPCR (for diagnostics), genomics (genomic DNA, transcriptome), reporter arrays, tissue genomic mapping, and epigenomics. Market analyses support the idea that the single-cell genomics market is currently sustained by academic funding but that it is about to transition towards a wider customer base with an overall market that should reach the $1-2 Billion range around 2020. Our solution will be highly competitive because it addresses current technical issues and represents the innovation that will disrupt the market. Our method will enable the broad adoption of single-cell genomics by the biomedical and clinical communities and will capture a large share of the sample preparation for single-cell genomics market. 05/15/2016 Stony Brook University LIBH image of external link icon Diagnostic device Single-cell genomics Single-cell genomics Available Peter Donnelly
Developing a small molecule drug to treat systemic C. albicans infections Nicholas Carpino Systemic candidiasis caused by fungal Candida species is becoming an increasingly serious medical problem for which current treatment is inadequate. Recent work has established the Sts phosphatases as key negative regulators of the host anti-fungal immune response. Significantly, genetic inactivation of Sts-1 dramatically enhances survival of mice infected with Candida. Importantly, the Sts-/- phenotype is associated with reduced fungal burdens, sharply diminished levels of many inflammatory molecules beginning at 24 hours post infection, a reduction in organ leukocyte infiltrates, and an absence of inflammatory lesions. To significantly improve patient outcomes, we plan to develop small molecule inhibitors of Sts-1 as immuno-stimulatory therapeutic agents for the treatment of systemic candidiasis. In the proposed studies, we will establish the druggability of Sts-1, demonstrate the feasibility of our approach and lay the foundation for a larger scale drug discovery effort. We will accomplish our goal by conducting a pilot-scale targeted screen of pharmacologically active compounds and determine the X-ray crystal structures of human Sts-1 in complex with inhibitors and substrate analogs. The successful completion of the proposed studies will enable us to assess the viability of Sts-1 as a drug target, provide leads for further development and provide a structural framework from which to rationally develop and optimize Sts-1 inhibitors 05/15/2016 Stony Brook University LIBH image of external link icon Small Molecule Drug treatment of C. albicans infections Candida Available Peter Donnelly
Next generation hedgehog inhibitor for invasive basal cell carcinoma Jiang Chen Vismodegib is the first-in-class hedgehog (Hh) pathway inhibitor for the treatment of locally advanced and metastatic basal cell carcinomas (BCCs). Systemic use of Vismodegib provided an unprecedented solution for invasive or inoperable BCCs. However, only 30-40% eligible patients responded to Vismodegib, and treatment resistance developed within months of treatment. The next generation Hh inhibitors, which act downstream of Smo, are expected to be able to overcome drug resistance. Recently, it was discovered that the processing of Gli transcription factors, direct targets of the Hh signaling pathway, is reliant on the intraflagellar transport (IFT) machinery. We found that some components of IFT function exclusively in the Hh pathway, and disrupting genes encoding these IFT proteins can block the formation of BCC in vivo, suggesting that these IFT proteins are attractive therapeutic targets. In this proposal, we aim to screen small molecule inhibitors of specific IFT proteins and determine whether IFT inhibitors can suppress the Hh signaling pathway and block BCC progression. We anticipate that IFT inhibitors can achieve comparable therapeutic efficacy to Vismodegib. More importantly, IFT inhibitors may be used to treat BCCs that do not exhibit initial respond to Vismodegib, or BCCs that develop resistance to Vismodegib. 05/15/2016 Stony Brook University LIBH image of external link icon Small Molecule Drug inhibitors of 1FT27 in Hh signaling and blocking BCC formation Basal cell carcinoma (BBC) Available Peter Donnelly
A novel strategy for recombinant AAV vector production for gene therapy Patrick Hearing Recombinant Adeno-Associated Virus (rAAV) vectors hold tremendous promise for a variety of gene therapy applications including gene delivery to the liver, skeletal muscle, central nervous system, the eye, among other target tissues. Currently, several different approaches are utilized to produce rAAV vectors. Most prominent among these are transfection approaches using plasmids that express gene products required for rAAV production, or virus infection approaches using herpesvirus or baculovirus vectors that express gene products required for rAAV production. Each of these approaches, however, has a significant limitation in the process of rAAV production. We recently described a recombinant Adenovirus (Ad) that contains a computationally redesigned gene encoding the AAV2 Rep protein. The AAV Rep protein is required for different aspects of rAAV production. Previous attempts to generate Ad vectors that contained the AAV Rep gene resulted in highly unstable recombinant viruses. Our results provide a basis to construct an entirely novel Ad-AAV hybrid that may be used for efficient rAAV production. The goal of this proposal is to assess the functionality of different Ad-AAV hybrid virus designs and the efficacy of their use is producing a rAAV vector for human gene therapy. 05/15/2016 Stony Brook University LIBH image of external link icon Other (gene therapy vector) Produce rAAV vectors using a novel ad-AAV hybrid virus Gene therapy applications Available Peter Donnelly
A tandem-integration-based multi-barcode method for high-throughput combinatorial screening Sasha Levy We will build prototypes and collect data to support a patent application that Stony Brook OTLIR is pursuing based on technology we developed. This technology can be applied to any cell type to generate and assay millions of combinations of DNA elements in cell pools using DNA barcodes and next generation sequencing. Because this technology acts as an interaction sequencing platform, it will have broad applications in basic research and industry including high-throughput protein or genetic interaction screens, double gene deletion screens, drug screens, and candidate gene identification screens. We have a working prototype of this system in the yeast Saccharomyces cerevisiae. Our specific aims are to: 1) Perform a proof-of-principle experiments in yeast to demonstrate the scalability of this system 2) Develop and test the technology in two human cell lines 3) Develop and test a murine embryonic stem cell that can be used to generate mice compatible with our technology 05/15/2016 Stony Brook University LIBH image of external link icon Other (research tool) Interaction DNA sequencing platform DNA sequencing Available Peter Donnelly
fMRI dynamic phantom for improved detection of resting-state brain networks Lilianne Mujica-Parodi The Stony Brook Dynamic Phantom is designed to perform two functions that would markedly increase data quality in newer task-free (“resting-state”) functional magnetic resonance imaging (fMRI), which depends more critically upon subtle features of time-series dynamics than do earlier task-based paradigms. First, the phantom will provide quantitative feedback to users in optimizing fMRI acquisition parameters for dynamic fidelity. Second, the phantom will identify scanner-induced distortion produced for a particular set of acquisition parameters, and then will employ algorithms to automatically correct that distortion. These functions will enable fMRI users both to increase detection sensitivity of resting-state brain networks, as well as to normalize data sets across scanner platforms. Building upon a working prototype of the phantom (patent pending), Year 1 of the POC targets key pre-commercialization hardware and software milestones necessary to increase precision, accuracy, reliability/reproducibility, and usability. Once these objectives are achieved in the POC phase, subsequent work (funded via either via REACH’s Commercialization Award or a STTR/SBIR) will focus on advanced algorithm/software development, adapting the phantom design to a universal standard and good manufacturing practice (GMP) for mass production, consumer field-testing of 25-50 devices, and incorporation of consumer feedback. We anticipate completion of both phases in 2-3 years, at which point the Stony Brook Dynamic Phantom will be manufactured and distributed commercially by ALA Scientific Instruments Inc., a Long Island small business. 05/15/2016 Stony Brook University LIBH image of external link icon Other (research tool) Functional magnetic resonance imaging Brain Available Peter Donnelly
Novel CAIX targeted combination inhibitor/PET tracer to treat patients with solid tumors Peter Smith-Jones Nearly 600,000 Americans die annually from cancer; ~90% secondary to solid tumor metastasis. Low oxygen (hypoxia) occurs as tumors outgrow their blood supply triggering blood vessel growth (angiogenesis) and tumor spread. For the past two decades, angiogenesis has been a major oncology target. However, results from clinical trials with angiogenesis-targeted inhibitors are disappointing. In contrast, therapies where an indicator of the drug target (i.e. biomarker) is combined with drug to select patients for therapy have proven more successful. The estrogen, HER2, and epidermal growth factor receptors exemplify this companion biomarker/targeted drug approach. We, and others, have identified carbonic anhydrase IX (CAIX) as a biomarker of tumor adaption to hypoxia and mechanism of drug resistance. CAIX, a transmembrane protein, is responsible for maintaining cellular pH in response to hypoxia. Without CAIX, cells cannot survive hypoxia and die. Many solid tumors adapt to hypoxia by inducing CAIX. We propose to evaluate five novel small molecules for the selective binding to and inhibition of CAIX activity. Our goal is to establish the feasibility that one or more of our small molecules can be developed as both a PET tracer (biomarker) and inhibitor (therapeutic) for non-invasively monitoring and sensitizing solid tumors to hypoxia-inducing therapies. 05/15/2016 Stony Brook University LIBH image of external link icon Combination (diagnostic and therapeutic) PET tracer (biomarker) and inhibitor (therapeutic) Solic cancer tumors Available Peter Donnelly
Substrate-Assisted Tethered Inhibitors of LigA to Treat MDR Gonorrhea Peter Tonge Novel therapeutics are urgently needed to treat sexually transmitted infections caused by antibiotic-resistant Neisseria Gonorrhoeae. In this project we will develop inhibitors of the N. Gonorrhoeae DNA Ligase LigA which is a validated target for antibacterial discovery. Our innovative approach utilizes substrate-assisted tethered inhibition (SATI) in which a small molecule is designed to bind to the enzyme-AMP intermediate and form a covalent adduct with the AMP. The inhibitor gains affinity from existing interactions between the AMP and the enzyme, thus allowing small drug-like molecules to be utilized. Since the compounds are designed to bind after the NAD+ substrate, the mode of inhibition will be uncompetitive, thereby circumventing the normal mechanism of LigA resistance to competitive inhibition in which mutations reduce the substrate Km. In addition, since the compounds will form an adduct with an existing covalent enzyme-substrate complex, the inhibitors are expected to have a long residence time on the target thus improving their therapeutic window by leading to continued target suppression even at low drug concentrations. This will enable dosing regimens that will improve patient compliance. To achieve our goals, we will synthesize a series of compounds that our modeling and preliminary data indicate bind to the LigA-AMP intermediate. We will profile the compounds using enzyme and whole cell assays to identify uncompetitive LigA inhibitors with antimicrobial activity towards drug-resistant strains of N. Gonorrhoeae. To ensure that these compounds are selective and non-toxic, we will counter screen our novel LigA inhibitors against the human DNA ligase and eukaryotic cell lines. These proof of concept studies will provide a foundation for securing additional funding, such as through the STTR mechanism or the POC or Commercialization Award Programs, enabling the assessment of in vitro and in vivo DMPK and the identification of proprietary chemical matter suitable for preclinical optimization. 05/15/2016 Stony Brook University LIBH image of external link icon Small Molecule Drug Inhibitor Neisseria Gonorrhoea bacterial infections Available Peter Donnelly
A novel 3-dimensional high-throughput screening assay for targeting invasive cancer cells Yizhi Meng (Originally Cao) The ability of cancer cells to invade into surrounding matrices is a critical determinant of metastasis. Despite considerable investment in cytotoxic drug discovery, their limited use against solid tumors coupled with their failure to prevent metastasis has reinforced the unmet need of targeting cancer invasion. In an effort to expedite the overall drug screening process, considerable efforts have been focused on development of practical three-dimensional (3D) cell culture platforms for drug discovery. However, 3D cell-based assays have not yet been incorporated into mainstream drug development programs that target metastatic process (e.g., cancer cell invasion). The goal of this proposal is to convert our unique 3D invasion assay to a high-throughput screening (HTS) platform for commercial use in pharmaceutical industry for drug screening. We hypothesize that developing a practical, simple, and cost effective 3D HTS invasion assay will facilitate identification of inhibitory compounds for preventing cancer metastasis. This hypothesis is based on our success in developing a 3-D invasion assay using a novel invasion plate. Since cell invasive behavior also occurs in other pathological conditions, our 3D drug discovery platform developed in this proposed study will accelerate drug discovery not only for cancer metastasis but also vascular and inflammatory diseases. 11/01/2016 Stony Brook University LIBH image of external link icon Other (drug screening tool) Drug screening tool Cancer cell invasion Available Peter Donnelly
The MELD computer method for discovery Ken Dill CHANGE IN SPECIFIC AIMS: We had three initial specific aims in our project plan: (1) Documentation, training, user interface; (2) Scaling up native-structure finding with experimental data and (3) Cloud access. After attending the StartUp bootcamp at the Stony Brook business developing center we have revised our aims to better align with our business model. Our goal is to tackle the steps needed for us to incorporate as quickly as possible. We have changed aim (1) to better reflect how we want to protect our IP and the fact that we are going to be a Contract Research Organization (CRO) rather than a software support/licensing company. We have also geared aim 2 to look more at the interactions between biologicals and proteins, which is a niche with little to no competition of particular strategical importance to our business partners and customers (Merck, Jansen, Zymeworks, …). The new aims are: Specific aim 1: Maintenance and streamlining of MELD protocols. Specific aim 2: Increase of functionalities that are of interest to pharma. Specific aim 3: Cloud Access. ORIGINAL AIMS: We have developed MELD, a powerful new computer method for drug discovery. Computational Physical Modeling (CPM) is used widely in pharma and biotech to discover new drugs. But CPM has limited accuracy and is computationally expensive. MELD goes beyond CPM in speed and accuracy to solve critical needs: computing protein structures without using databases, assisting in determining experimental protein structures with limited data, finding the binding poses and sometimes affinities, of complex molecules bound to proteins. With pilot funding that we received from a big pharmaceutical company, and a joint publication with them in preparation, we have a proof of concept (POC) for MELD in peptide-protein binding. That company now seeks to license MELD. We are in discussions with other pharma and biotech companies. Our milestones here are: (i) to create documentation and user interfaces, so the code can be licensed and used by others, (ii) to extend the method for a key application: obtaining protein structures from limited experimental data and (iii) to make it readily available for cloud computing through Amazon Web Services. Our deliverable will be MELD code that is useful by others for drug discovery. Ken Dill and Alberto Perez have over 60 years of combined experience in computational structural biology. Dill has had roles with previous start-ups, and on scientific advisory boards. 12/01/2016 Stony Brook University LIBH image of external link icon Other (research tool) Software for simulating biomolecules Available Peter Donnelly
Asymmetric Dual-screen active matrix flat panel x-ray imagery Anthony Lubinsky The proposed project addresses the need for a low cost/high quality/low dose detector for digital radiography. The solution is based on a unique and novel x-ray detector configuration in which two inexpensive x-ray screens composed of granular phosphor material in a binder are sandwiched around a light detector array deposited on an optically thin substrate. The project aims to demonstrate feasibility by building and testing a prototype device and comparing results against theoretical predictions. There is an intermediate milestone on experimental test arrays, and a final milestone on prototype assembly and testing. The team is strong, with the PI having many patents and long industrial experience in the design of related products. 12/01/2016 Stony Brook University LIBH image of external link icon Diagnostic Device x-ray detector configuration Available Peter Donnelly
Targeted Anti-Thrombotic Drug Delivery Using Engineered DNA Nano-Carriers Oren Rotman Presently over 5.8 million patients suffer from congestive heart failure in U.S. and their number is expected to grow by 46% by 2030. Of those, a significant proportion will become candidates for mechanical circulatory support devices and prosthetic heart valves - all burdened with thromboembolic risk which mandate life-long anticoagulant medication therapy. While conventional pharmacological therapy aims to suppress the pro-thrombotic features of these devices, it is applied systemically and affects the entire circulation, therefore exposes the patients to risks of bleeding and toxicity. In the proposed project, a novel technology for targeted antithrombotic drug delivery is introduced. The technology is based on shear-stress –sensitive DNA nano-carriers that flow in the blood stream and release their cargo (drug) when exposed to disturbed shear stresses that characterize such devices. The aim is to specifically deliver the drug to target sites, without exposing the patients to risk of bleeding. The immediate goal of the project is to demonstrate feasibility of the DNA nano-carriers to be activated by prescribed shear stresses. The long term goal is to provide proof of concept in-vivo, eventually replacing current standard of care with precision medicine antithrombotic drug therapy. 12/01/2016 Stony Brook University LIBH image of external link icon Other (Targeted drug delivery) Nanotechnology Congestive heart failure Available Peter Donnelly
Novel Radiotracers to Image Infection in Humans using Positron Emission Tomography Peter Tonge Treatment of bacterial infections in humans is hindered by the relatively unsophisticated diagnostic methods that are currently available, some of which are either slow or inaccurate and often depend on the availability of clinical samples that contain bacteria. The long-term objective of this proposal is to develop radiotracers that can be used to rapidly detect and localize bacterial populations in various human diseases using positron emission tomography (PET). PET is a noninvasive technique that has had a profound impact on the ability to detect, diagnose and study disease in humans especially in the areas of neuroscience and oncology. The utility of PET depends on the availability of radiolabeled compounds that distribute in the human body in a way that informs on the specific disease condition. In order to apply this technique to infection imaging, a radiotracer is required that accumulates selectively at the site of infection. In this Feasibility proposal we will explore the ability of a fluorine-18 labeled bacterial metabolite to accumulate in Staphylococcus aureus and image a soft tissue model of S. aureus infection. These studies will then be extended to a model of S. aureus endocarditis. Infective endocarditis (IE) has a high mortality rate partly because a definitive diagnosis cannot be reached at an early stage of infection. The availability of a PET tracer that can diagnose IE is expected to dramatically improve the ability to effectively treat this important infectious disease. The goal of the Feasibility proposal is to demonstrate that our novel fluorine-18 radiotracer is superior to FDG for detecting IE. 12/01/2016 Stony Brook University LIBH image of external link icon Diagnostic Device Diagnosis infective endocarditis Available Peter Donnelly
Carbon-based nanoparticle delivery of nucleic acid expressing anti-amyloidogenic myelin basic protein (MBP) peptide to neurons to test feasibility of a novel approach to Alzheimer's therapy William van Nostrand Alzheimer’s is a neurodegenerative disease characterized by accumulation of toxic amyloid-beta (Abeta) and tau pathology, and myelin dysfunction in the brain. The few drugs currently approved for Alzheimer’s modulate brain neurotransmitter signaling but do not meaningfully alter disease trajectory. Multiple drugs targeting Abeta pathology have failed in clinical trials because of their (1) inability to achieve efficacious levels of drug in the brain through peripheral administration without systemic toxicity, and/or (2) stimulation of deleterious immune responses. Therefore, administration of a non-immune-based Abeta-targeting drug directly to the brain should overcome both of these limitations. Towards this aim we propose testing feasibility of combining two technologies developed at Stony Brook University to produce a therapeutic agent for mild Alzheimer’s, i.e., anti-amyloidogenic myelin basic protein (MBP) peptide expression with an established carbon nanoparticle-based gene delivery system. MBP peptide inhibits and/or reverses Abeta fibril formation in vitro, and significantly reduces Abeta and associated cognitive deficits when transgenically expressed in the brain of Alzheimer’s model mice. As an initial key step in developing a novel, intranasal-administered, MBP-based Alzheimer’s therapy, in the current proposal we seek to test delivery of MBP peptide-expressing gene to cultured primary neurons using the established carbon nanoparticle delivery system. 12/01/2016 Stony Brook University LIBH image of external link icon Biologic Drug 1) MBP peptide as therapeutic agent and 2) O-GNR nanoparticle delivery system Alzheimer's disease Optioned Peter Donnelly
BRIKARD, a program for macrocyclic drug discovery Evangelos Coutsias Macrocycles (MCs) are the fastest growing class of new drugs. Their studies have undergone a rebirth over the last few years, fueling a burst of business activity of both large biotech companies (Merck, Pfizer) and startups founded in the last 5 years (Bicycle, Ensemble, Oncodesign, etc.) with the aim to extend the repertoire of available MC drugs. Computational methods for artificial MC candidates screening are the essential part of these studies. Unfortunately, computational methods developed for small molecules or for proteins are resource demanding, and they perform poorly for macrocycles. In the proposed project, we develop a new approach based on our BRIKARD algorithm that numerically solves the sampling problem and demonstrates superior performance and efficacy compared to currently used approaches. Our deliverable will be the software package that predicts conformations of artificial MCs and their interaction with target proteins using either fully de novo approach, or in a combination with a limited set of experimental data (e.g., NMR derived). Drs E. Coutsias and M.Wester, the developers of BRIKARD algorithm, have an extensive experience in computational molecular biology algorithm development, M. Lukin hasan expertise is NMR of biomolecules, and D. Kozakov is an in silico docking expert 05/01/2017 Stony Brook University LIBH image of external link icon Combination (Small molecule drug, biologic drug, research tool) Computational tools for design and development of artificial macrocycles Available Peter Donnelly
Tyrosine Phosphatase-Sigma Inhibitors for Hematopoietic Regeneration John P. Chute M.D. Systemic therapies which can promote the self-renewal or regeneration of hematopoietic stem cells (HSC) in vivo could have broad therapeutic benefits for patients receiving myelosuppressive chemotherapy or radiotherapy, those undergoing hematopoietic cell transplantation, and for patients with aplastic anemia. We have discovered a unique transmembrane protein tyrosine phosphatase (PTP), PTP-sigma, which is expressed by murine and human HSCs and which strongly regulates HSC regeneration in vivo. Based on our findings, we have developed several PTP-sigma inhibitors with novel composition of matter and have demonstrated that systemic administration of such PTP inhibitors promote hematopoietic regeneration in vitro and in vivo. We propose here to perform the critical efficacy studies in mice and against human HSCs to develop a lead PTP-sigma inhibitor capable of accelerating human hematopoietic regeneration in patients receiving myelosuppressive chemotherapy or radiotherapy and patients undergoing hematopoietic cell transplantation. 08/01/2016 UCLA UC-CAI image of external link icon Small molecule drug PTP-sigma inhibitor Self-renewal or regeneration of hematopoietic stem cells (HSC) Available Ragan Robertson
Engaging human NK cells to kill cancer with trispecific biologics Daniel Vallera, PhD To develop trispecific NK cell engagers to activate the immune cell at the site of the cancer allowing high specificity for killing cancer with minimal damage to normal cells. 01/01/2016 University of Minnesota MN-REACH image of external link icon Biologic Drug IL-15 TRiKES (Trispecific NK cell Engagers) acute myelogenous leukemia (AML); myelodysplastic syndrome (MDS) Licensed Raj Upuda
Rapid antimicrobial susceptibility testing from a colony (rapid AST) Valerie Pierre, PhD To develop a technology that enables rapid antimicrobial susceptibility testing from a colony in less than an hour. 03/01/2016 University of Minnesota MN-REACH image of external link icon Diagnostic Device Rapid point-of-care diagnosis for bacterial infection in high-risk inpatient population Bacterial infection Available Raj Upuda
Stem Cell-derived islets for treatment of type 1 diabetes Meri Firpo, PhD To demonstrate proof-of-concept of an encapsulated stem cell-derived islet product for treatment of diabetes. 04/01/2016 University of Minnesota MN-REACH image of external link icon Biologic Drug Stem cell-derived islets Type 1 Diabetes Available Raj Upuda
Reducing sepsis-related mortality in cancer patients through microbiome therapy Dan Knights, PhD To develop a rapid early diagnostic method to predict incidence of bloodstream infection in patients undergoing chemotherapy by evaluation of patient microbial DNA. 04/01/2016 University of Minnesota MN-REACH image of external link icon Combination Probiotic and dietary therapies to reduce the risk of bloodstream infections in patients undergoing hematopoietic stem cell transplants (HSCT) and diagnostic to determine at-risk patients Bloodstream infections in patients undergoing HSCT Available Raj Upuda
MMG22, a potent analgesic for chronic inflammatory pain associated with metastic/primary bone cancer Philip Portoghese, PhD To evaluate optimal routes of delivery of MMG22, a potent analgesic without tolerance 04/01/2016 University of Minnesota MN-REACH image of external link icon Small Molecule Drug Antihyperalgesic with mild opioid receptor binding Cancer Pain Available Raj Upuda
CD8 T cell immunotherapy to functionally cure HIV Pamela Skinner, PhD To provide proof-of-concept for a CXCR5/CAR immunotherapy that targets the follicular reservoir of HIV-producing cells 04/01/2016 University of Minnesota MN-REACH image of external link icon Biologic Drug CD8 T cell immunotherapy HIV/AIDS Available Raj Upuda
PET molecular imaging probe for epidermal growth factor receptor: Precision medicine in cancer treatment through patient stratification Benjamin Hackel, PhD This imaging technology provides a non-invasive method to rapidly analyze the whole body for identification and characterization of epidermal growth factor receptor (EGFR) expressing primary and metastatic tumors. Monitoring the EGFR expression level on cancer cells allows for both better treatment planning and a predictive response to current therapies and identify non responders. 10/01/2016 University of Minnesota MN-REACH image of external link icon Diagnostic Device PET molecular imaging probe for epidermal growth factor receptor Cancer-colorectal, breast Licensed Raj Upuda
Commercialization of a Tissue-Engineered AV Graft Robert Tranquillo, PhD A decullularized tissue graft for arterio-venous access in patients requiring dialysis for end stage renal disease. This decellularized tissue graft would decrease failure and infection rates of current dialysis access methods. 10/01/2016 University of Minnesota MN-REACH image of external link icon Therapeutic Device Off-the-shelf tisuue-engineered arteriovenous graft End-stage renal disease (blood dialysis) Licensed Raj Upuda
Peripherally restricted combination opioid therapy for chronic inflammatory, neuropathic or cancer pain George Wilcox, PhD This peripherally-acting opioid analgesic will decrease the risk for addiction and abuse while still alleviating pain. 10/01/2016 University of Minnesota MN-REACH image of external link icon Small Molecule Drug Peripherally restricted combination opioid therapy Post-operative pain Available Raj Upuda
Micrometer: Developing Robust Clinical Diagnostic Assays for the Microbiome Kenny Beckman, PhD This project will develop clinical-grade technologies that bring rigor and accuracy to microbiome profiling, allowing the development of a clinical diagnostic assay that will enable microbiome-based clinical therapies. 03/01/2017 University of Minnesota MN-REACH image of external link icon Other Standardized microbiome profiling n/a Licensed Raj Upuda
Preclinical studies of intranasal benzodiazepine prodrug/converting enzyme systems for rapid rescue from seizure emergencies Ronald Siegal, PhD This project will develop a nasal spray as a rescue therapy for seizure emergencies, which delivers drug in an aqueous vehicle, to be administered by the patient or a caregiver outside of the emergency department whenever and wherever a seizure cluster occurs (e.g. home, work, school etc). The product will have improved tolerability, exhibit faster, more consistent absorption, and an earlier onset of action compared to other rescue therapies, either approved or under development. 06/01/2017 University of Minnesota MN-REACH image of external link icon Combination Intranasal benzodiazepine prodrug/converting enzyme systems Seizure emergency Available Raj Upuda
A Nanophotonic Platform for Rapid and PCR-free Detectionof Bacterial and Fungal Infection Ian Kennedy, PhD The goal is to develop a multiplex, rapid, point-of-care diagnostic platform and assay for in vitro detection and identification of bacterial and fungal DNA using whole blood collected from a venous draw. 08/01/2014 UC Davis UC-CAI image of external link icon Diagnostic device POC diagnostic for in vitro detection of bacterial/fungal DNA Disseminated Intravascular Coagulopathy (DIC) or other signs and symptoms of sepsis in the ICU patients, and suspected culture-negative endocarditis. Available Robin Stears
Advanced Development of Intravenous Oxygen Microparticles Brian Polizzotti The goal of this project is to create injectable, hollow core, injectable microparticles which carry oxygen gas for the purpose of intravenous oxygen delivery. Oxygen is utilized at the mitochondrial level for energy production. Even when brief, tissue hypoxia stimulates a cascade of injury, inflammation and apoptosis which, on a tissue level, causes organ injury, dysfunction and death. The goal of this technology is to prevent the 'oxygen debt' which causes these cascades by creating a therapeutic to acutely raise tissue oxygen tension via the intravenous route. This concept is distinct from blood substitutes (including hemoglobin- and perfluorocarbon-based technologies) which require an intact lung unit to oxygenate the blood substitute; this technology, by contrast, introduces the oxygen gas directly into the bloodstream where it diffuses into surrounding plasma and tissues. In proof of concept work, our group has shown that phospholipid-based microbubbles filled with oxygen gas can delivery sufficient oxygen to sustain life for 15 minutes without a single breath (Kheir, Science Translational Medicine, 2012; also, see TED talk). The work we propose in this grant will advance this technique by creating a microparticle shell which optimizes oxygen carrying capacity, shelf stability and the safety of injection; the advances will enable critical features, such as filtration and rapid intravenous injection. Because tissue hypoxia is central in the pathogensis of many critical illnesses, this technology is likely to revolutionize medicine. The technology will likely be life-saving in many clinical situations, including acute lung injury, cyanotic congenital heart disease and acute anemias; however, we anticipate that the first clinical indication would be for cardiac arrest, a disease in which cessation of systemic blood flow causes profound tissue hypoxia. We have shown (in swine testing) that the addition of oxygen microparticles to bystander CPR improves cerebral oxygen delivery and survival in an otherwise mortal disease. This work has been funded by multiple sources, including Boston Children's Hospital Technology and Innovation Office, CIMIT (including the Young Clinician Award to Dr. Kheir, a co-PI on this grant), DOD, AHA and philanthropy. BCH has filed 7 provisional patents on the technology, the first of which has been granted. The resources of B-BIC will be instrumental to the successful translation of this technology to the bedside, which requires mulitdisciplinary (likely multi-institutional) expertise, including those with engineering, pharma, regulatory, and VC expertise. We look forward to collaborating with you. 04/01/2015 Boston Children's Hospital BBIC image of external link icon Therapeutic Device Systemic oxygen deprivation caused by acute respiratory failure Available Ron Blackman
MicroRNA Antisense Therapeutics in Cardiometabolic Diseases Anders Naar We have discovered several microRNAs implicated in cardiovascular disease, obesity, and type 2 diabetes. Our in vivo studies in mice and non-human primates have validated once-weekly subcutaneous injection of antisense oligonucleotides (antimiRs) specifically targeting these microRNAs as potent and safe therapeutics ameliorating circulating cholesterol/lipid abnormalities that predispose to cardiometabolic diseases. We aim to take these antimiRs into further rodent and non-human primate efficacy and IND-enabling safety studies prior to human Phase I studies. 04/01/2015 Massachusetts General Hospital BBIC image of external link icon Biologic Drug Cardiometabolic disorders and nonalcoholic steatohepatitis (NASH) Available Ron Blackman
Targeting erythropoietin-based therapeutics - Pilot Pamela Silver This proposal aims to test a targeted erythropoietin (EPO)-based therapeutic in mice. EPO plays multiple biological roles by binding to EPO receptors on diverse cell types, including erythroid progenitors,macrophages, pro-megakaryocytes, cancer cells, and neurons. The therapeutic goal of this work is to minimize the side effects of EPO by targeting this protein to red blood cell (RBC) precursors and away from other cell types. Recombinant EPO has been used for two decades to treat various forms of anemia associated with endstage renal failure, AIDS, chemotherapy, or hemoglobinopathies. Clinical use of EPO has decreased in recent years due to concerns over the drug’s off-target effects: EPO treatment has been linked to tumor recurrence and platelet formation or activation, which may lead to coronary disease or thrombosis. Targeting EPO to RBC precursors to specifically ameliorate symptoms of anemia while avoiding side effects should bring significant patient benefit by allowing higher doses to fully restore RBC levels without increasing the risk of cardiovascular events. In addition, the targeted EPO developed here should have an extended serum half-life and reduced immunogenicity relative to existing EPO drugs. 05/15/2015 Harvard Medical School BBIC image of external link icon Biologic Drug Anemia Available Ron Blackman
Activated Platelet Time: an improved factor VIII assay Gary Gilbert Factor VIII activity assays are necessary to diagnose patients who have hemophilia A, to monitor treatment dosing of these patients, to determine when inhibitory antibodies against factor VIII have developed, and to evaluate the activity of engineered pharmaceutical factor VIII products. Factor VIII activity has been measured with evolving one and two-stage assays for fifty years. However, all existing assays have major shortcomings that are recognized by FDA, the International Society for Thrombosis and Haemostasis, and pharmaceutical companies. The major deficiencies are: 1) In the presence of inhibitory antibodies, factor VIII asssays do not predict the risk of bleeding. The degree of inhibition in assays is less than required to explain patient bleeding. 2) The assays are only accurate over a range of 1 – 100% of normal factor VIII activity, while values of 0.1 - 1% are also clinically important. 3) The different approved assays give discrepant values for recombinant pharmaceutical factor VIII products, with a range of 2-fold difference between assays. This can lead to clinically important differences in dosing of factor VIII products from one region to another with corresponding risk of thrombosis or bleeding. 07/01/2015 Boston VA Medical Center BBIC image of external link icon Other Factor VIII-related hemophilia Available Ron Blackman
Novel antibody targeting approach for the treatment of idiopathic pulmonary fibrosis Edgar Milford IPF, being the most common and lethal form of idiopathic interstitial pneumonitis, is a life-threatening disease, characterized by progressive scarring of lungs accompanied by decreased oxygen uptake. Patients with IPF experience shortness of breath. There are no approved treatments for IPF. IPF is associated with a median survival time of 2 to 5 years and a 5-year survival of 20–40%, a mortality rate higher than that of a number of malignancies, e.g. colon cancer. Approximately two-thirds of patients die within five years after diagnosis. The cause of IPF remains elusive and its pathogenesis incompletely understood. The development of fibroblastic areas in the lung and the accumulation of inflammatory cells are hallmarks of IPF. Patients are often treated with immunosuppressive drugs; with no improvement of survival or quality of life. Thus, a combined prevention of fibrosis and inflammation could stabilize lung function diminishing the impact of this devastating disease. Anti-TIRC7 antibody targets a highly specific mechanism that has evolved to regulate lymphocyte activation with the potential to treat inflammatory conditions, e.g. IPF or rheumatoid arthritis. The selective mode of action of the anti-TIRC7 antibody combined with an encouraging risk–benefit profile distinguishes anti-TIRC7 mAbs from other immuno-modulatory drugs holds the promise to contribute significantly to IPF disease treatment. 12/01/2015 Brigham and Women's Hospital BBIC image of external link icon Biologic Drug Idiopathic pulmonary fibrosis Available Ron Blackman
Elimination of pathogenic IgE in cystic fibrosis John Connor Allergic bronchopulmonary aspergillosis (ABPA) causes worsening of the respiratory condition in patients with cystic fibrosis (CF) and leads to bronchiectasis, fibrosis and loss of lung function. Treatment of ABPA also carries risk, as it can result in steroid dependency and serious adverse events. Reduction of pathogenic IgE has been shown to improve respiratory symptoms and lung function in ABPA. We are developing a novel biologic drug that has a dual mechanism: reduction of systemic IgE and inhibition of IgE-mediated pathological responses. We predict our drug will be highly efficacious in reducing lung damage in CF. 02/01/2016 Boston University BBIC image of external link icon Biologic Drug Allergic bronchopulmonary aspergillosis in cystic fibrosis patients Available Ron Blackman
Novel Approaches for Platelet Storage Karin Hoffmeister The overall goal is to optimize storage conditions of platelets at room temperature (22°C) in platelet additive solutions using glycosidase inhibitors to increase availability, safety and efficacy of platelet transfusions. The current FDA restricted shelf life (< 5 days) of room temperature stored platelets seriously limits platelet availability, drives donor recruitment efforts and leads to significant wastage of this critical resource and of health care dollars. In 2011, a total number of 2,169,000 platelet units were transfused in the United States1, of which 321,070 apheresis platelets [12.8%] valued at nearly $172 million [$535.17 each] expired.1 In patients with hypoproliferative thrombocytopenia, who use about 80% of stored platelet components and receive chronic platelet transfusion predominantly for prophylaxis, post-transfusion increments, survival time, and durable hemostatic efficacy are important; however, platelet transfusion alone does not prevent bleeding. Solutions to increase platelet shelf life and at the same time to prevent platelets from deteriorating during storage will not only improve the provision of platelets to patients, but will increase safety and efficacy of platelet transfusions. 06/01/2016 Brigham and Women's Hospital BBIC image of external link icon Other Blood platelet storage Available Ron Blackman
Targeting Erythropoietin-Based Therapeutics DRIVE Pamela Silver This proposal aims to test a targeted erythropoietin (EPO)-based therapeutic in mice. EPO plays multiple biological roles by binding to EPO receptors (EPO-R) on diverse cell types, including erythroid progenitors, macrophages, pro-megakaryocytes, cancer cells, and neurons. The therapeutic goal of this work is to minimize the side effects of EPO by targeting this protein to red blood cell (RBC) precursors and away from other cell types. Recombinant EPO has been used for two decades to treat forms of anemia associated with end-stage renal failure, AIDS, chemotherapy, or hemoglobinopathies. Clinical use of EPO has recently decreased due to concerns over the drug’s off-target effects: EPO treatment has been linked to tumor recurrence and platelet formation or activation, which may lead to coronary disease or thrombosis. Targeting EPO to RBC precursors should allow higher doses to fully restore RBC levels without increasing the risk of cardiovascular events or cancer progression. In addition, the targeted EPO developed here should have an extended serum half-life and reduced immunogenicity relative to existing EPO drugs. 08/01/2016 Harvard Medical School BBIC image of external link icon Biologic Drug Anemia Available Ron Blackman
Silencing Airway Nociceptors for Treatment of Cough and Airway Inflammation Bruce Bean Cough is the most common reason patients see their primary care physician and the sixth most common reason for hospital-based outpatient care. Cough is poorly treated by currently available therapeutics, including opioids, dextromethorphan and benzonatate. Coughing is initiated reflexively when nociceptors (pain fibers) innervating the upper airways are stimulated, principally by activation of ion channels expressed by these sensory fibers including the transient receptor potential (TRP) channels V1 and A1 channels. We have developed a novel treatment for cough based on selective delivery of permanently charged cationic sodium channel blockers into activated airway nociceptors through activated TRPV1 and TRPA1 ion channels, which are selectively expressed by nociceptors. Using the tool compound QX-314 (N-ethyl-lidocaine) delivered as an inhaled aerosol, we have shown that this approach can inhibit cough in a guinea-pig model, as well as dramatically reducing airway inflammation in a mouse asthma model. We have now synthesized novel compounds that block neuronal sodium channels more potently than QX-314 and propose to test these in a guinea pig cough model. We will also initiate pharmacokinetic studies to verify the expected lack of systemic exposure with delivery of the cationic compounds in inhaled aerosols. We expect this approach of completely but selectively electrically silencing airway nociceptors to be much more effective than alternative approaches such as inhibiting only P2X3 or TRPA1 channels and believe that the mechanism and features of the technology make it ideally suited for translating from guinea pigs to human patients. 10/01/2016 Harvard Medical School BBIC image of external link icon Small Molecule Drug Cough Available Ron Blackman
Novel Treatment for Long QT Syndrome David Milan Long QT syndrome is a genetic disease, caused by mutations in cardiac ion channels, that affects otherwise healthy individuals resulting in an increased risk of sudden cardiac death. Patients are diagnosed by electrocardiogram and history and confirmed by genetic testing. The sole pharmacologic therapy is beta-blocking agents which reduce cardiac events, but are incompletely effective with 25% of patients going on to have fainting or sudden death. Implantable defibrillators are used for the highest risk patients, but these devices carry significant risks and complications over time.2 Despite knowledge of the genetic, molecular, and physiologic basis for this disease for over 20 years, we still have no FDA approved therapy that addresses the underlying problem of the prolonged QT interval. Prior efforts have suffered from the liability of producing a drug-induced short QT syndrome which is as dangerous as long QT syndrome itself. Our laboratory has discovered a novel compound class that shortens the QT interval in multiple long QT models.6 Unlike previous efforts, our compound, 2MMB, displays a self-limited effect on the QT interval that prevents the short QT syndrome. The target is the ATP sensitive potassium channel. Affected long QT patients would take this medication indefinitely to correct the pathophysiology and reduce the risk of sudden death. Long QT syndrome is at the upper end of orphan disease size which promises to facilitate a rapid path to drug registration. 02/01/2017 Massachusetts General Hospital BBIC image of external link icon Small Molecule Drug Long QT syndrome Available Ron Blackman
Shear-Activated Nanothrombolytic - Nanovasodilation Donald Ingber The goal of this project is to develop a shear-stress activated vasodilator for the prevention and treatment of artery spasm, in particular the prevention of radial artery spasm during transradial catheterization procedures and the prevention and treatment of cerebral vasospasm following a subarachnoid hemorrhage. The DRIVE grant will support the next 21 months of research and early preclinical development. The specific objectives of this project are: (1) nanoparticle (NP) formulation development and in vitro analysis (tranche 1), (2) NP aggregate (NPA) formulation development (tranche 2) and (3) in vivo NPA studies (tranche 3). Successful completion of these studies will result in a locked-in product design, which should enable us to obtain follow-on funding to move to GLP-production of vasodilator-NPAs, carry out full toxicology testing using the GLP materials, and progress to first-in-man clinical studies. NP Formulation Development and In Vitro Analysis (Months 1-12): A shear-stress activated vasodilator will be prepared by encapsulating a known small molecule vasodilator in poly(lactic-co-glycolic acid) (PLGA) nanoparticles using methods which are well established in our laboratory. The choice of vasodilator will be governed by its pharmacological profile and its solubility in aqueous and organic solvents. We will primarily focus on calcium channel blockers (CCBs) and nitric oxide (NO) donating drugs, all of which are off patent and can be multi-sourced. The lipophilic nature of PLGA NPs will favor lipophilic drugs resulting in higher drug loading and stability. The deliverables for this initial stage of the project are (i) optimized preparation and purification of API encapsulated NP test lots (100-150 mg NP/lot), (ii) encapsulation efficiency >75%, particle size <300nm, loading >5%, (iii) in vitro testing of API release (physiologically relevant release during 60 min in PBS buffer, BSA or serum conditions) and (iv) analytical method development (LC-MS). Our aim is to prepare and test three to 5 different vasodilator NPs and then decide which one(s) to advance to the next stage of development. NPA Formulation Development (Months 13-18): Following lead selection, one or several vasodilator NPs will be spray dried into NPA formulations using methods that are well established in our laboratory. The use of excipients will allow us to fine-tune the shear stress sensitivity of the NPAs that we will test using low energy ultrasound and/or using microfluidic devices. The deliverables for this stage of the project are (i) scale-up manufacturing of NPA formulation (50-100mg/lot), (ii) demonstrate desired shear breakability performance and (iii) develop targeted NP/NPA formulations and validate drug release profile. In Vivo NPA Studies (Months 16-21): Once NPA formulations of selected vasodilators have been developed and tested, one or several selected leads will be scaled up and tested in rabbit and/or juvenile pig artery vasospasm models established at CBSET, Lexington, MA. Over the course of the next few months, we will discuss the details about the animal models with CBSET and obtain the respective approvals. The deliverables for this stage of the project are (i) scale-up manufacturing of NPA formulation (500 mg NPA/lot) and (ii) obtain clinically relevant vasodilatory effect in a rabbit or juvenile pig artery vasospasm model (CBSET). 03/01/2017 Harvard Medical School BBIC image of external link icon Biologic Drug Radial artery spasm Available Ron Blackman
PR1P, an inhaled novel short peptide for emphysema Benjamin Matthews Emphysema is a chronic progressive pulmonary disease characterized by destruction of alveoli leading to impaired oxygenation and retention of carbon dioxide that threatens human health worldwide. Disease progression is due in part to dysregulation of the survival factor Vascular Endothelial Growth Factor (VEGF). Emphysema has no cure: there are no drugs to prevent disease progression or restore lung tissue to health. We recently designed a novel 12 amino-acid peptide, PR1P, that upregulates endogenous VEGF, and that based on recent preliminary data we hypothesize could be used in humans to treat emphysema. The peptide requires proof of principle testing in animal emphysema models. Thus, our solution to this problem is an inhaled pharmaceutical (PR1P) that targets and stabilizes endogenous VEGF in the lungs to enhance VEGF signaling and restore lung health. We propose here to characterize the effect of PR1P on emphysema progression in an established 3-week duration murine elastase-induced emphysema model. Mice will be treated with inhaled PR1P (or scrambled peptide), and we will characterize the effects of PR1P on 1) lung mechanics, 2) lung function, and 3) lung architecture during disease progression. Our hypothesis is that PR1P mitigates elastase-induced emphysema progression in murine lungs. Our goal at the completion of this one-year project is to show that PR1P mitigates elastase-induced emphysema in mice. If our hypothesis is correct, then this project plan will provide the proof of principle necessary to support further development of PR1P for use in larger animals and then humans to treat emphysema. 06/01/2017 Boston Children's Hospital BBIC image of external link icon Small Molecule Drug Emphysema Available Ron Blackman
Targeting a Novel Neurodegeneration Mechanism to Develop a New Therapeutic Approach to Alzheimer's and ALS Mark Albers Neurodegenerative diseases, including Alzheimers disease, have no known therapies. In analogy to the cancer field, we believe that disease pathways may be shared across neurodegenerative diseases, and the clinical expression of these cascades is an instantiation of unique factors for each patient: 1). the location in the nervous system where the pathway arises, 2). the genetic landscape, and 3). environmental factors (including epigenetic changes and somatic mutations). Defining a pathway in one neurodegenerative disease may be relevant in a subset of patients with different neurodegenerative diseases. We have recently discovered a new mechanism of propagated neurodegeneration in mice fitting this paradigm. We validated it in human brain tissue from AD and ALS cases, recapitulated it in cultured human neurons, identified 8 small molecules that rescue neurodegeneration. Our overall goal is to develop a series of targets and lead compounds that are coupled with a biomarker that identifies patients where this innate immune mechanism is operative and that serves as a pharmacodynamic marker of target engagement. 07/01/2017 Massachusetts General Hospital BBIC image of external link icon Small Molecule Drug Alzheimer's and ALS Available Ron Blackman
Pro-resolving micro-/nano-particles to improve vascular patency Matthew Spite 09/01/2016 Brigham and Women's Hospital BBIC support for UC-CAI-led project image of external link icon Therapeutic Device This work is conducted in conjunction with UCBraid PI Michael Conte as the lead Available Ron Blackman
Hydrogel device for preventing cardiac adhesions post-cardiothoracic surgery. Karen Christman Reoperations in cardiac surgery have increased surgical risks due to cardiac adhesions, which increase the difficulty of sternal reentry, hinder visibility of mediastinal tissues, and increase potential injury to cardiovascular tissues. This leads to an increased risk of surgical bleeding and increased length of the surgical procedure, which increase patient morbidity and mortality. This is especially relevant for pediatric patients with congenital heart defects who will experience multiple surgeries over their lifetime. Cardiac adhesions have also become a common problem in adults who experience multiple surgeries to repair or replace valves or to undergo coronary revascularization procedures. Two main approaches exist for reducing or attempting to prevent cardiac adhesions: pharmacological therapy and physical barriers. Drugs that prevent or reverse adhesion processes disrupt biochemical pathways of inflammation and fibrin deposition. Unfortunately, these processes are also vital for wound healing. Achieving adequate drug concentration at the site of action is also challenging. A more viable approach is the use of a physical barrier to prevent fusion of the heart to surrounding tissues. The barriers can be either preformed membranes or injectable hydrogels (fast gelling liquids). Preformed anti-adhesive materials need to be cut before application to the tissue, and must be sutured into place to prevent slippage. While they can help with sternal reentry, they do not prevent cardiac adhesions and do not reduce dissection times. Injectable hydrogels allow the freedom of applying material where needed applying the precursor components and are capable of quickly forming a protective gel over the surface of the tissue. While a variety of different materials have been investigated in animals and humans, no materials, to date, have been capable of preventing adhesion formation post-cardiac surgery without risking deterioration of cardiac function. Herein, we propose a new approach to prevent postsurgical cardiac adhesions using rapidly forming poly (ethylene glycol) (PEG) hydrogels that are cross-linked by oxime bonds. Oxime bond formation is the reaction between hydroxyl amines and ketones/aldehydes, and will be used to both crosslink the material and attach it to tissue. Our approach is a two component polymeric system that can be easily applied directly onto the heart forming an anti-adhesion layer within seconds. With this system we can control the degree of swelling and degradation time to prevent adhesions yet not interfere with cardiac function. As part of this proposal, we will demonstrate proof-of-principle for using the PEG oxime system to prevent cardiac adhesions in a rat cardiac surgery model. Following successful completion of this study, GMP manufacturing of the material will be performed along with ISO 10993 biocompatibility tests and a porcine study with the GMP material. In combination with the studies proposed herein, this is anticipated to fulfill the requirements for an IDE submission (PMA pathway). All studies will be performed according to GLP guidelines to facilitate FDA submissions. This will also provide sufficient data to license the technology. 08/01/2015 UCSD UC-CAI image of external link icon Therapeutic device Hydrogel device Cardiac adhesions Available Rose Murphy
Gene-modified mesenchymal stem (stromal) cells for the Treatment of the Acute Respiratory Distress Syndrome Michael Matthay, MD Project focuses on development of a novel therapeutic based on enriched conditioned media from bone derived mesenchymal stem cells which have been transfected with secreted proteins which enhance efficacy for treatment of acute respiratory distress syndrome 02/01/2015 UCSF UC-CAI image of external link icon Biologic Drug Enriched conditioned media from bone derived mesenchymal stem cells Acute Respiratory Distress Syndrome Available Saunders Ching
Oral THU-decitabine, a novel non-cytotoxic epigenetic therapeutic Yogen Saunthararajah, MD Researchers at the Cleveland Clinic are developing a novel therapeutic combining the FDA approved drug decitabine with the cytidine deaminase inhibitor tetrahydrouridine (THU) for the treatment of Sickle Cell Disease (SCD), a genetic disorder that affects approximately 80,000 Americans. SCD is caused by an abnormality in the oxygen-carrying protein hemoglobin that leads to several acute and chronic health problems such as severe infections, attacks of severe pain, stroke and a decreased life expectancy. Currently, the only FDA-approved drug for SCD is Hydroxyurea, which is effective in only about two-thirds of people with the disease. A Phase I study has demonstrated that combination therapy with THU-decitabine is safe and increases normal hemoglobin levels in patients with SCD that did not previously respond to treatment with Hydroxyurea. A limitation of this combination therapy, however, is that the current intravenous formulations require patients to repeatedly come to the hospital to take the prescribed dose of medicine. The project is directed to development of an easy-to-swallow, time-released oral dosage form of THU-decitabine which has the potential to provide a much-needed therapeutic option for patients suffering with SCD in a form that will make it easier for patients to keep up with their needed medication at home. 08/01/2014 Cleveland Clinic Foundation NCAI-CC image of external link icon Small molecule therapeutic Sickle Cell Disease Licensed Suguna Rachakonda
Novel Anti-inflammatory Drug Targeting NOX2 in Acute Lung Injury (ALI) Yi Zheng, PhD Researchers at the CCHMC are developing a novel small molecule anti-inflammatory drug for treatment of acute lung injury (ALI), which is characterized by rapid and severe respiratory failure, arising after major surgery, trauma, or multiple transfusions. ALI occurs in nearly 200,000 patients a year in the United States with a mortality of greater than 50%. The current treatment option for patients with ALI is ventilation, which is limited in its benefit. Cumulatively, ALI patients spend 3.6 million days in the hospital annually, with a cost of $150-250K per hospitalization. A primary driver for ALI is the release of reactive oxygen species (ROS) by activated neutrophils that result in irreversible organ damage. The Zheng lab has developed a novel small molecule drug (NOX2-I) that inhibits ROS production by neutrophils and significantly reduces lung inflammation in clinically relevant pre-clinical ALI models. This project focuses on further defining the drug-like properties of a potential NOX2-I lead compound through additional pharmacokinetics, toxicity and efficacy studies in pre-clinical ALI models with the goal of advancing into IND-enabling studies. The development of a new generation anti-inflammatory therapy for ALI has the potential to address a large unmet clinical need in an untapped market that is estimated to exceed $1 billion annually. 08/01/2014 Cincinnati Children's Hospital Medical Center NCAI-CC image of external link icon Small Molecule Therapeutic Acute Lung Injury Available Suguna Rachakonda
A small molecule inhibitor of 15PGDH markedly accelerates hematopoietic reconstitution following hematopoietic stem cell transplantation Sanford Markowitz, MD. Researchers at CWRU have developed SW033291, a novel first-in-class small molecule that has been shown in pre-clinical rodent models to accelerate recovery of platelets, red cells, and neutrophils by up to 6 days following bone marrow transplantation. Annually, more than 60,000 hematopoietic stem cell transplants (HST) are done worldwide, with more than 20,000 performed in the United States. The use of HST is steadily increasing, based on its potential for correcting hemoglobinopathies, bone marrow failure syndromes, and storage diseases. Treatment costs can be as high as $160,000 with patients undergoing HST experiencing long hospital stays and increased risks of infection, excessive bleeding and other transplant related complications. The potential for SW033291 to accelerate hematopoietic reconstitution by up to 1 week may save lives as well as reduce cost by up to $40,000 per HST. Successful development of SW033291 has the potential to significantly improve outcomes for a growing HST market that is currently estimated in excess of $3 billion per year. 08/01/2014 Case Western Reserve University NCAI-CC image of external link icon Small Molecule Therapeutic Blood Disorders Licensed Suguna Rachakonda
EYA Inhibitors in the Treatment of Peripheral Vascular Disease and PAH Rashmi Hegde, Ph.D. Researchers at Cincinnati Childrens Hospital Medical Center are developing a novel EYA tyrosine phosphate inhibitor as a small molecule druggable option for the treatment of pulmonary arterial hypertension (PAH). There is a large unmet need to identify new therapeutic targets in the treatment of PAH, a progressive, life threatening disorder. Approximately 50% of patients diagnosed with PAH die within 5 years. Current treatments do not inhibit pulmonary remodeling, a key pathology of PAH. Furthermore, they are associated with significant hospitalization cost. EYA protein plays a fundamental role in promoting survival of cells after DNA damage. Recent evidence points to a role of DNA damage repair in PAH in pulmonary remodeling. The goal of this project is to validate a small molecule treatment for pulmonary arterial hypertension (PAH) that targets a newly identified molecular pathway involved in survival of hypoxia-damaged cells, hence addressing the molecular basis for the vascular remodeling in PAH. 03/01/2015 Cincinnati Children's Hospital Medical Center NCAI-CC image of external link icon Small molecule Therapeutic Pulmonary Artery Hypertension Available Suguna Rachakonda
Development of small molecule inhibitors specific for IL-17A mediated pulmonary inflammation Xiaoxia Li, PhD Asthma is a major chronic disease ranging from mild to severe refractory disease. Severe asthma is difficult to treat and frequently requires high doses of systemic steroids. In some cases, severe asthma even responds poorly to steroids. Elevated levels of IL-17A have been detected in asthmatic lung tissues and are positively correlated with neutrophil-predominant severe and steroid-resistant asthma. Deficiency of IL-17A signaling components leads to diminished neutrophilic pulmonary inflammation and airway hyper-responsiveness (AHR) in both allergic- and non-allergic asthma mouse models. Therefore, IL-17A signaling is a promising therapeutic target for inhibiting IL-17A-dependent pulmonary inflammation, particularly for the treatment of severe and steroid-resistant asthma. Through computer-aided virtual screening based on the crystal structure of IL-17 RA/IL-17A complex, Dr. Li and colleagues have identified a small molecule lead compound, A18, which has exhibited excellent ability to inhibit IL-17A binding to IL-17RA in animal models. The project is directed to validate and optimize the small molecule lead and derivatives for better bioactivity. The goal is to develop this new non-steroidal small molecule product, to be developed for oral delivery, to treat patients with severe, inadequately controlled, or steroid-resistant asthma by targeting a novel immune/inflammatory pathway. 03/01/2015 Cleveland Clinic Foundation NCAI-CC image of external link icon Small molecule therapeutic Asthma Available Suguna Rachakonda
Inhibition of CD40-TRAF Signaling for the Treatment of Vascular Inflammatory Disorders Carlos Subauste, MD. Researchers at CWRU are developing small molecules that inhibit CD40 signaling that results in vascular inflammation. A broad range of diseases are characterized by vascular inflammation, including neointima formation after arterial injury, atherosclerosis, allograft rejection, ischemia/reperfusion induced tissue injury, inflammatory bowel disease, microvascular complications of diabetes, lupus, rheumatoid arthritis and other autoimmune diseases. CD40 is a protein found on antigen-presenting cells and is a target for the treatment of various vascular inflammatory disorders; however inhibition of CD40 signaling may induce immunosuppression. TNF Receptor Associated Factors (TRAF) are major mediators of signaling downstream of CD40. Inhibition of CD40-TRAF2 signaling may control inflammation and cause less immunosuppression than generalized CD40 inhibition. The project is directed towards development of a small molecule therapeutic that prevents CD40-TRAF2 interaction and significantly inhibits CD40-driven pro-inflammatory responses at low concentration. The drug has been shown to be non-toxic in mice, effectively diminishes inflammation in animal models of inflammatory bowel disease, and does not increase susceptibility to an opportunistic pathogen. Drug optimization with the goal of developing a lead compound will initially be evaluated in preclinical models focused on important cardio-vascular diseases including venous graft failure after coronary artery by-pass surgery, failure of arteriovenous fistula in patients on hemodialysis and vasculopathy after organ transplantation. The development of a CD40-TRAF2 small molecule inhibitor has the potential to address a broad variety of inflammatory and autoimmune diseases driven by CD-40 through an approach that minimizes the risk of immunosuppression. 03/01/2015 Case Western Reserve University NCAI-CC image of external link icon Small Molecule Therapeutic Vascular Inflammation Available Suguna Rachakonda
Development of a Method to Store Refrigerated Platelets for Human Transfusion Jose Cancelas, MD, PhD Researchers at CCHMC have identified novel chemical inhibitors that allow for cold storage of platelets beyond the current standard of five days. Cancer and trauma therapy frequently require platelet transfusion support, especially in the context of leukemia therapy and bone marrow transplantation, and in war situations. Platelet products have a 5-day nominal shelf life, but it is actually 2.5-3 days due to FDA mandated testing for microbiological contamination. This short shelf-life limits the availability of platelet products and results in out-dating 20-30% of collections. Approximately 3 million doses of platelets are used in USA every year that account for sales of ~$1.5 Billion annually. Significant portions of these are lost due to deterioration of the samples. Several studies have shown a family of proteins knows at Rho GTPases may play a significant role in platelet deterioration during storage. The Cancelas lab has developed a novel combination of Rho GTPase inhibitors that, when added to storage media, have the potential to extend platelet survival to seven days or beyond. The demonstration of successful, refrigerated storage of platelets for 7 days or longer would dramatically change the current practice of platelet transfusion in the world. The development of a proprietary media resulting in longer and more stable platelet storage will save the industry several hundred million dollars in lost samples and significantly improve the supply chain associated with providing patients much needed platelet transfusions. 08/01/2015 Cincinnati Children's Hospital Medical Center NCAI-CC image of external link icon Therapeutic Platelet Transfusions Available Suguna Rachakonda
Evaluating Synthoplate Technology in Porcine Traumatic Bleeding Anirban Sen Gupta, Ph.D. Researchers at CWRU have developed a novel synthetic platelet technology that will obviate reliance on donor-derived platelets, the availability of which are limited due a very short shelf life (~3-5 days) and a high risk of bacterial contamination. Platelets are blood cells that are primarily responsible for creating ‘hemostatic plugs’ at sites of blood vessel injury (both internal and external) to reduce bleeding, facilitate coagulation and subsequent healing. Platelet transfusions are routinely used in the clinic to prevent bleeding-associated morbidities and mortalities in patients with hematologic and oncologic platelet disorders, chemo/radio-therapy induced bone marrow suppression (myelosuppression) and trauma or surgery-associated heavy bleeding. There are an estimated 3 million platelet transfusions a year making for a nearly $2 billion annual market, yet demand for platelets is anticipated to significantly exceed supply owing to their short shelf life, high risk of bacterial/viral contamination, and transfusion-related immunogenicity. The proposed technology is directed towards addressing the unmet clinical need of an in vitro manufactured intravenously injectable synthetic platelet that leverages and amplifies endogenous clotting mechanisms for efficient management of bleeding complications. In vivo studies have shown that SynthoPlate demonstrated enhanced hemostatic efficacy compared to past synthetic platelet designs. Successful development of an effective synthetic platelet technology will provide several benefits over existing platelet replacement strategies, including (i) high availability due to scalable manufacturing, (ii) no need of blood-type matching due to being a synthetic product, (iii) low risk of contamination due to efficient sterilization, (iv) much longer shelf-life as lyophilized powder product, and (v) possibly low biologic side-effects due to biocompatible and biodegradable components. 09/01/2015 Case Western Reserve University NCAI-CC image of external link icon Combination product Platelet Transfusions Available Suguna Rachakonda
Advancing Rapid Malaria Detection Technology Towards Commercialization Brian T. Grimberg, PhD Researchers at CWRU are developing a cost-effective, rapid, diagnostic for malaria detection that can be deployed in a point-of-care setting. Approximately half of the world’s population is at risk of malaria, a life-threatening disease caused by Plasmodium parasites and transmitted by mosquitoes. Malaria is preventable and curable, and early diagnosis and treatment of malaria prevents deaths and reduces transmission. Malaria is most common in developing countries such as Asia, Latin America and Africa. Current rapid detection methods (using microscopy) take ~1 hr to make an accurate diagnosis but this method incorrectly identifies the presence of malaria more than 50% of the time. For greater sensitivity, time-consuming PCR or expensive antibody dipstick cells are necessary. Preliminary laboratory data indicates that the blood diagnostic being developed by the Grimburg lab can quantify the level of parasites in a blood sample in under 1 minute, for $0.09 per sample, with an accuracy of 94%. Enhancements to the design to be pursued in this project may enable improvement that could decrease the current minimum detectable level by 5 fold, thereby providing the possibility of identifying asymptomatic malaria carriers, and curtailing spread of malaria infection. 02/01/2016 Case Western Reserve University NCAI-CC image of external link icon Diagnostic Malaria Licensed Suguna Rachakonda
HemeChip: Point-of-Care Sickle Cell Disease Diagnosis in Low Resource Settings Umut Gurkan, Ph.D. Researchers at CWRU have developed a low-cost, point-of-care diagnostic tool to detect sickle cell disease (SCD), a genetic disorder that results in abnormalities in the oxygen-carrying protein hemoglobin leading to several acute and chronic health problems such as severe infections, attacks of severe pain, stroke and a decreased life expectancy. Sickle cell disease (SCD) is common throughout much of sub-Saharan Africa, affecting up to 3% of births in some parts of the continent. An estimated 50-80% of the babies born with SCD in Africa die before the age of 5 due to lack of diagnosis. Unfortunately current diagnostic methods for SCD are too expensive or time consuming for broad accessibility in low resource countries such as Africa. It is estimated by the World Health Organization (WHO) that, 70% of SCD related deaths are preventable with simple, cost-efficient interventions that could be made available with better diagnosis. HemeChip is a low-cost screening test for SCD (and other hemoglobin disorders), that can be performed in less than 10 minutes. HemeChip technology is based on electrophoresis methods that have been well established and have been widely applied in SCD diagnosis for well over 40 years. HemeChip testing has shown that it is extremely robust, accurate and reliable compared to existing SCD diagnostic tools. The technology is being developed to provide a low-cost, easily accessed SCD diagnostic that could be used to screen the nearly 20 million new births each year in sub-Saharan Africa, which thereby has potential to save millions of lives through earlier therapeutic intervention. 02/01/2016 Case Western Reserve University NCAI-CC image of external link icon Diagnostic Sickle Cell Disease Licensed Suguna Rachakonda
Development of IV Probenecid for ADHF Jack Rubinstein, MD Researchers at the University of Cincinnati are reformulating the orally administered generic drug probenecid for intravenous (IV) delivery to patients with acute decompensated heart failure (HF). Chronic HF affects more than 5 million patients in the United States, creating a healthcare burden of more than $30 billion in direct costs. Acute decompensated HF is a sudden worsening of heart failure symptoms that contributes significantly to the more than 1 million HF related hospitalizations a year and is a powerful predictor for re-hospitalization and death. Probenecid has been used for decades for the treatment of gout with a proven safety record. Recent studies have demonstrated that it also serves to improve cardiac contractility (positive inotrope) without the significant adverse effects commonly associated with other inotropic drugs, such as cardiac cell death, hypertrophic enlargement, or arrhythmias. Probenicid acts as a potent agonist to a calcium channel recently discovered in isolated cardiomyocytes (TRPV2). In a study Ten HF subjects that were enrolled in a double-blinded, randomized, placebo-control, cross-over study demonstrated that probenecid treatment improved cardiac function as measured by ejection fraction (p=0.01) with trends toward improvement in exercise tolerance. These benefits were observed in patients already on optimal-medical therapy. An IV formulation will have the potential advantage of providing greater bioavailability and a more rapid response in patients with acute decompensated HF. 02/01/2016 University of Cincinnati NCAI-CC image of external link icon Small molecule therapeutic Heart Failure Licensed Suguna Rachakonda
Small Molecule Inhibitors of Ezrin to Target Inflammation and Airway Contraction in Asthma Neetu Gupta, PhD Asthma is a chronic and heterogeneous disease in which immune cells collaborate with smooth muscle cells to induce airway inflammation and hyper-responsiveness. Researchers at Cleveland Clinic have found that a small molecule targeting the membrane-cytoskeleton linker protein Ezrin inhibits inflammation and airway contraction associated with asthma. The team has also seen that small molecule-mediated inhibition of ezrin in tracheal rings significantly lowers smooth muscle contraction, and thus has a strong potential for reducing airway hyper-responsiveness. The overall goal of this project is to develop a proprietary lead compound with potent inhibitor activity against Ezrin with optimized pharmacological profile. A treatment that ameliorates both asthmatic inflammation and smooth muscle hyper-responsiveness at the cellular level could be extraordinarily potent. Preliminary observations indicate that this may be such a treatment. 08/01/2016 Cleveland Clinic NCAI-CC image of external link icon Small Molecule Therapeutic Asthma Available Suguna Rachakonda
Regenerative Therapeutics for Treatment of Acute Myocardial Infarction Jerry Silver, PhD Acute Myocardial Ischemia (AMI) affects 7.6 million people in the USA each year, with over 45 million survivors suffering functional disabilities, including risk for arrhythmia and heart failure. Recent studies have identified sympathetic denervation in the vicinity of the scar as a predictor of arrhythmia susceptibility. This project takes a novel approach to developing an effective treatment for myocardial ischemia by targeting the electrical innervation of the scarred myocardium utilizing a novel peptide, Intracellular Sigma Peptide (ISP). Success of this overall approach may lead to permanent improvements in cardiac function, potentially reducing the risk of sudden cardiac death and eliminating long-term pharmacological treatment regimens. ISP has been shown in preclinical studies to regenerate cardiac nerves into the infarcted myocardium and to prevent arrhythmia susceptibility. The project focuses on further characterization of preclinical safety, toxicology and pharmacokinetic analysis in preparation for advancing to future efficacy studies in large animal trials. 08/01/2016 Case Western Reserve University NCAI-CC image of external link icon peptide therapeutics Myocardial Infarction Available Suguna Rachakonda
Inhibition of Arginine Methylation as a Therapy for Asthma Mireia Guerau-de-Arellano, PhD Current asthma therapies are based on non-specific immunosuppression with steroids and management of symptoms with bronchodilator drugs. In contrast, there are almost no drugs that precisely target the inflammatory responses underlying asthma. Dr. Guerau’s team is developing a small molecule inhibitor of the arginine methyltransferase enzyme PRMT5 for the treatment of asthma. The selective PRMT5 inhibitor, HLCL65 (5μM IC50), has demonstrated in vivo efficacy in a T cell inflammatory disease model to inhibit certain inflammatory T helper cell (Th1, Th2, Th17) responses while maintaining beneficial regulatory T cell (Treg) activity. The development goal is to obtain additional proof-of-principle in vivo efficacy data for further development and lead optimization of PRMT5 inhibitors as an asthma therapy. Drugs that have suppressive effects on inflammatory T helper cell (Th1, Th2, Th17) responses while maintaining or enhancing regulatory T cell (Treg) responses would be a considerable improvement over current therapies. 11/01/2016 Ohio State University NCAI-CC image of external link icon small moleculetherapeutic Asthma Available Suguna Rachakonda
Calcineurin Inhibitors for Treatment of Acute Respiratory Distress Syndrome Dehua Pei, PhD The project will evaluate the drug properties of three newly developed peptidyl inhibitors against calcineurin in vitro as well as their in vivo efficacy for treatment of acute respiratory distress syndrome using a mouse model. 01/01/2017 The Ohio State University, Department of Chemistry and Biochemistry NCAI-CC image of external link icon Therapeutic ARDS Available Suguna Rachakonda
Preventing Long-term AV Graft Infection Through an Rechargeable Antibiotic Coating Horst A. von Recum, PhD Developing an arteriovenous graft which is capable of preventing device infection for use in hemodialysis patients with end-stage renal failure. Infection is one of the leading causes of AV graft failure, with risk increasing over time. No graft with the capability of long-term prevention or treatment of device infection exists. Our technology has proven antimicrobial function which can be recharged in vivo for additional therapeutic windows as needed. 01/01/2017 Case Western Reserve University, Department of Biomedical Engineering NCAI-CC image of external link icon Combination product Dialysis Access Available Suguna Rachakonda
A novel mucolytic treatment for lung disease John V. Fahy MD This program is to develop a novel mucolytic treatment for mucus pathology in airway disease. Highly elastic mucus is difficult to clear and it results in airflow obstruction and airway infection, but there are currently no mucolytic drugs that can be given to patients by hand held inhaler. We recently discovered a mechanism of oxidant-induced increases in mucus elasticity that identifies excessive numbers of mucin disulfide bonds as a therapeutic target in stiff mucus gels. We are optimizing a series of inhaled mucolytics for Cystic Fibrosis, COPD and asthma. 08/01/2015 UCSF UC-CAI image of external link icon Small Molecule Drug Mucolytic drug Mucuous Disease of the Lung, (COPD, cystic fibrosis, asthma) Available Sunita Rajdev
A first-in-class RalGEF inhibitor as an anti-Ras drug Geoffrey J. Clark This application proposes the development of new agents to block the activities of the Ras oncoprotein. Ras is activated in over 50% of cancers, notably lung and pancreatic. Historically, attempts to target activated Ras itself and the Ras pathway have failed. The PI has a new strategy involving small molecule blockade of the interaction between Ras and the guanine nucleotide exchange factors of the Ras-like (Ral) small GTPases (RalGEFs). Using in silico screening, the PI has identified at least one lead compound (C4) which has been derivatized. They have demonstrated interaction by immunoprecipitation and it shows activity against soft agar colony growth and metastatic spread of pancreatic cancer (with no effect on growth of the primary tumor) with a lack of toxicity in vitro and in vivo. The small molecule was able to inhibit metastasis in vivo in preliminary animal experiments. A provisional patent application for the method of use was recently filed; however, Technology Transfer believes it will also be possible to obtain composition of matter intellectual property. This proposal looks to show actual binding of the small molecule and protein and provide additional rounds of medicinal chemistry. The proposal follows standard procedures of development and optimization, and pharmacokinetic and toxicity studies will be outsourced. The applicants have outlined 4 milestones with go/no-go decisions: 1) Quantification of target binding; 2 additional rounds of Medicinal Chemistry and Optimization/bioassay screening. No-go decision: If target binding cannot be validated. 2) Further 2 rounds of medicinal chemistry optimization; large scale synthesis of the best two optimized compounds for use in vivo, and analysis of the compounds biological effects on metastatic processes in vitro. No-go decision: If compounds cannot be scaled up. 3) Determination of MTD of the “5th generation” C4 derivative; full in vivo toxicity; characterization and PK studies via commercial entity. No-go decision: Adverse toxicity or very poor PK. 4) Test the optimized compounds at their MTD in xenografts experiments using Ras driven pdx metastatic lung tumor systems, including comparison with Cisplatin treatment as a standard of care and examination of effects on metastasis. No-go decision: Failure to suppress tumor development/metastasis. The expected outcome is the identification of a fully validated preclinical lead compound within the funding period of 2 years. The PI has 25 years’ experience and >70 publications in the Ras biology field. The team consists of the head of the molecular modeling core facility at the university and performed the initial in silico screen which identified the active compound. He has broad experience in the development and validation of small molecule inhibitor compounds from bench to bedside with two drugs derived in this manner entering clinical trials. Additional team members consist of a Medicinal Chemist and a Molecular Biologists with experience with molecular biology of cancer and in vivo mouse systems. 02/01/2016 University of Louisville UofL - ExCITE image of external link icon Small Molecule Drug Ral GEF inhibitor Lung Cancer Available T. Allen Morris
Development of SMASH technology as a next-gen sequencing diagnostic for congenital heart disease Michael Ronemus Congenital heart disease (CHD) occurs in roughly 1 out of every 1,000 live births and is one of the major causes of infant morbidity and mortality. Copy number variants (CNV) have been shown to play a key role in CHD, and an improved method of detection could provide geneticists with earlier information on the presence of potentially harmful (or helpful) mutations in newborn infants. Currently approved genomic tests carry significant label restrictions and deliver little informational utility to clinical geneticists. Dr. Michael Wigler and colleagues at Cold Spring Harbor Laboratories (CSHL) have developed technology for “Short Multiply Aggregated Sequence Homologies” (“SMASH”) which has the potential to provide a drastic improvement in detection of CNV with high throughput and low cost. The goal of this proposal is to benchmark the ability of SMASH to identify de novo and inherited CNVs in patients with CHD against previously generated microarray data leveraging a curated sample set of DNA from 223 families afflicted with CHD. The PI has worked extensively with the technology and is a longstanding collaborator of Dr. Wigler; the corporate co-sponsor/co-investigator is a serial entrepreneur with experience in building companies and commercializing novel technologies. 05/15/2016 Cold Spring Harbor Laboratory LIBH image of external link icon Combination (Diagnostic device and research tool) Sequencing Congenital heart disease Optioned Teri Willey
Profiling the human immune system with machine learning algorithms and bioinformatics software Gurinder Atwal Recent advances in DNA sequencing technology in bulk tissue and single cells are poised to dramatically transform our understanding of molecular biology and human health. In particular, sequencing the T cell and B cell repertoire in an individual has the potential to revolutionize immune-based diagnostics, vaccine profiling, and monoclonal antibody engineering. However, the development of powerful and accessible computational tools to analyze the diverse immune repertoire has lagged behind, preventing widespread adoption of immune sequencing in the bench and industry. Moreover, the prohibitive computational expertise needed to interpret the data has further stymied adoption of immune sequencing as a valuable diagnostic and prognostic in the clinic. We propose to develop commercial machine learning and bioinformatics software that will facilitate the processing and analysis of large complex data sets generated by sequencing many cells from the adaptive immune system. The intended users are biological researchers and clinicians. In this pilot project, computational biologists will work with experimental data to develop preliminary analyses of vast collections of single cell data and determine the feasibility of a commercial, powerful, and easy-to-use software service for users that will aid both diagnoses and development of effective immune-based therapies. 12/01/2016 Cold Spring Harbor Laboratory LIBH image of external link icon Combination (research tool, biological drug) Computational platform to analyze sequencing data to discern immune cell repertoire DNA sequencing Available Teri Willey
Targeting treatment-refractory myelodysplastic syndrome with small molecule drugs modulating novel hematopoietic progenitor self-renewal pathways Lingbo Zhang Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic malignances. MDS is characterized by anemia resulting from progressive bone marrow failure. Currently, the therapeutic options for MDS are very limited, and only a small fraction of patients benefit from standard erythropoietin and lenalidomide treatment. Our project focuses on treating these treatment-refractory MDS through boosting expansion of early erythroid progenitor, whose insufficiency contributes to resistance of MDS patients and more broadly the aging population to current therapies. We have employed a CRISPR/Cas functional genomic approach to screen all known druggable protein targets. We have identified a protein target and demonstrated the in vivo efficacy of its corresponding small chemical inhibitors in genetically engineered MDS mouse models and aging mouse models of completely correcting anemia with durable long-term response. In proposed research, we plan to collect in vivo dosage and pharmacokinetic (PK) parameters for a small chemical compound that better inhibits this protein target with improved selectivity and reduced toxicity, with which we will generate a new IP. The PI has extensive research background in molecular hematology with peer-review publications in journals including Nature, Genes and Development, and Blood. Our team member holds MS degree in Pharmacology and has extensive experiences in PK/PD studies and drug discovery 12/01/2016 Cold Spring Harbor Laboratory LIBH image of external link icon Small molecule drug chemical compounds to boost etythroid progenitor Myelodysplastic syndromes Available Teri Willey
Pro-Resolving micro-/nano-particles to improve vascular patency Michael S. Conte MD Development of a drug-loaded nanoparticle to test therapeutic actions and efficacy in in vitro, in vivo and ex vivo models of vascular restenosis 08/01/2016 UCSF UC-CAI image of external link icon Small Molecule Drug Small Molecule Drug in nanoparticle Artherosclerotic cardiovascular disease and peripheral arterial disease Available Todd Pazdera
Improving Outcomes of Cardiac Resynchronization Therapy Andrew McCulloch Cardiac resynchronization therapy (CRT) uses biventricular pacemakers to resynchronize ventricular contraction in an attempt to reverse the course of dyssynchronous heart failure. CRT device sales generated estimated revenue of $1.18 in North America in 2015. Companies such as Medtronic, Boston Scientific and St Jude Medical also market procedure planning and management tools, and these businesses are growing at approximately 10% annually. The valuation analysis for this new technology includes: (a) an improvement in CRT responder rate from 65 to 85%; (b) an increase in global implantation rates from under 40 to over 50%; (c) an expansion of CRT indications to include an additional 10% of systolic heart failure patients not currently indicated under the guidelines; and (d) and increase in market share as a result of these competitive advantages. The improvement assumed here in responder rates is modest compared with the results of our preliminary clinical studies. Based on high industry interest, our business plan assumes an exit strategy of selling this technology to a major medical device manufacturer that markets CRT devices, but it would also be feasible to bring a new product directly to the clinical market. This research project will test a novel clinical decision support system that predicts and optimize outcomes of CRT in patients with dyssynchronous heart failure by using machine learning algorithms trained with patient-derived computational models. The commercial product objective of this project is a patient-specific clinical decision support system that reads in routine clinical measurements (ECG and cardiac ultrasound images) and uses patent-pending model-derived algorithms to compute a predictive index of ventricular dyssynchrony. With NHLBI support, our research group and clinical collaborators have prototyped, filed IP protection for and tested in patients, new computational techniques for discriminating patients who are likely to respond to CRT from those who are not, have derived novel mode/¬based indices that strongly correlate with CRT outcomes. In this initial clinical study, this new method predicted patient CRT outcomes with over 95% accuracy. Currently, CRT patient-selection is based solely on clinical guidelines. There are no accepted predicted biomarkers for CRT response, and current criteria for pacing optimization do not have a mechanistic foundation. Consequently, there are no commercial competitors marketing or developing decision-support tools for predicting CRT outcome and optimization. Patient-specific computer simulations of cardiac function are virtually non-existent in clinical practice, and represent an under-developed yet cost-effective predictive tool with the ability to provide clinical data integration, decision support and therapy planning. This proposal will validate the ability of our patient-specific technology to quantitatively predict and optimize CRT outcomes in 100 retrospective heart failure patients, a sample size large enough to assess the statistical utility of these computer modeling predictions. The computation of the predictive biomarker will require only routine clinical assessments such as electrocardiograms and echocardiograms. The aims will test the ability of patient-specific dyssynchrony indices to improve patient responses by providing clinical decision support for optimizing pacing protocols to maximize cardiac functional improvement and reverse remodeling. A fully validated clinical simulation tool would dramatically improve the management of dyssynchronous heart failure in an expanding market, reduce unnecessary procedures, and improve effectiveness of an approved device therapy. 08/01/2016 UCSD UC-CAI image of external link icon Health information technology Patient-specific clinical decision support system Dyssynchronous heart failure Available William Decker
Automation of Photoplethysmographic Screening for Coarctation of the Aorta and Patent Ductus Arteriosus Robert Koppel The proposed work extends our earlier development of photoplethysmography (PPG)-based methods for detection of neonatal cardiovascular disorders. Coarctation of the aorta occurs in 112,500 newborns and is the critical congenital heart disease most likely to be missed before hospital discharge. Delayed diagnosis may result in cardiovascular collapse, neurologic injury, and death. Patent ductus arteriosus (PDA) occurs in 60% of preterm infants and is associated with significant morbidity. However, the clinical assessment of PDA is challenging. The intended customer is every hospital with a birth facility or NICU. The envisioned technology may be a free-standing device or it may add new biomarkers to existing cardiorespiratory monitors. The proposed work involves electrical and software engineering to digitally identify landmarks In PPG and EKG wavefonns and then automatically calculate and display clinical indices. The milestones include automating the selection of regions of interest, the calculations, and the validation of the automated measurements in clinical practice. The deliverables are ( 1) a prototype automatic three-channel single-wavelength PPG device displaying PPG-derived indices and (2) clinical pilot study data validating the automation. Our team's strength lies in Prof. Nitzan's experience in developing devices with automated PPG wavefonn interpretation and Dr. Koppel's experience with conducting related clinical trials. 12/01/2016 Feinstein LIBH image of external link icon Other (screening device) Coarctation of the aorta in the newborn Available
A Composite Biomarker Score Computer Aided Diagnostic Device (CBS-CAD) for Improved Prostate Cancer Management with Quantitative Multiparametric MRI Gregory Metger, PhD This software uses targeted magnetic resonance imaging of prostate cancer to create a map that identifies tumor location and extent of tumor spread. This software will minimize unnecessary prostate biopsies, reduce the risk of overtreatment, providing a non-biased modality to monitor prostate cancer. 10/01/2016 University of Minnesota MN-REACH image of external link icon Diagnostic Device Composite Biomarker Score Computer Aided Diagnostic Device (CBS-CAD) Cancer - Prostate Available
Development of a carbapenemase detection test Gina Thomson We have developed a test which rapidly detects gram-negative superbugs. These are antibiotic-resistant bacteria described by CDC as causing mortality comparable to Ebola. The most dangerous superbugs produce a carbapenemase enzyme which inactivates carbapenems (drugs of last resort) and related antibiotics. These organisms typically also contain mechanisms of resistance to most, sometimes all other antibiotics and comprise a major and increasing global health threat. In the USA they annually cause over 23,000 deaths and 2 million illnesses, with direct health care costs as high as 20 billion dollars plus the additional cost of 35 billion dollars through lost productivity and sick days. In 2012, 63% of U.S. infectious disease physicians reported having a patient infected with a totally resistant bacterial pathogen in the previous 12 months. Superbugs threaten both the therapy of infections as well as medical procedures that require antibiotics to protect patients from infection. Laboratory testing is critical. Physicians may have only one chance to successfully treat superbug infections. Unlike most bacterial infections, optimal therapy requires at least two active antibiotics to prevent the emergence and transmission of total antibiotic resistance and death of the patient. It is critical for laboratories to rapidly and accurately detect carbapenemase-producing superbugs to alert physicians of the need for combination therapy. Most laboratories use inaccurate phenotypic carbapenemase detection tests that require overnight incubation. A minority use accurate but inconvenient phenotypic tests or expensive PCR-based tests that have some unresolved accuracy problems. No current test is automated. There is an urgent and unmet need for rapid, accurate and convenient carbapenemase detection. Our test typically produces results within 1-30 minutes. It is accurate, inexpensive and can be manual or adapted to automation. In contrast to current phenotypic tests, it classifies carbapenemases into molecular groups, which is therapeutically important. The test is miniaturized and utilizes minimal inoculum, reagents and space. It was highly accurate in tests with well-characterized bacteria, some of which yield inaccurate results with current carbapenemase tests. Two years of developmental work and a budget of $200,000 are now needed to advance the test to the out-licensing stage. The market is approximately 2 billion dollars with customers comprising clinical, veterinary, government, pharmaceutical and diagnostic industry laboratories. Through their discoveries, publications and presentations, Gina and Kenneth Thomson have high profiles in antibiotic resistance research. Gina is the Antibiotic Testing Specialist and Lead Technologist for Infectious Disease Molecular Testing at the University of Louisville Hospital, and is a reviewer of manuscripts on antibiotic resistance for the Journal of Clinical Microbiology and for Antimicrobial Agents and Chemotherapy. Kenneth previously directed a premier academic antibiotic research team at Creighton University, Omaha, NE. 03/01/2017 University of Louisville UofL - ExCITE image of external link icon Diagnostic Device Carbapenemase detection kit Bacterial infection Available
Contingent music baby bottle Michael R. Detmer ""Feeding problems are prevalent in children, with 45% of typically developing, and up to 80% of children with disabilities being affected (Capilouto, 2016; Linscheid, 2003; Phalen, 2013). 50% of mothers claim at least one of their children eat poorly, which equates to approximately 20-30% of children (Kerzner, 2015). Feeding problems are most commonly attributed to the difficult transition from breast-feeding to bottle-feeding, prematurity, developmental disorders, and structural issues. One in three infants with feeding problems exhibit milk refusal from the bottle when they are transitioning from breast to bottle-feeding due to the mother needing to return to work or if her milk supply is not meeting the nutritional requirements of the infant (Levine, 2011). The proposed device will be used to address feeding issues in the first year of life, thus decreasing the incidence of later, more complex feeding and developmental problems including oral aversion, infantile anorexia, and speech and language delay. The device will be sold to and used by parents and feeding therapists including speech-language pathologists and occupational therapist in an outpatient setting. It will be used to address feeding problems such as bottle refusal and oral aversion in infants up to one year old. The device, which fits inside an existing baby bottle, provides the infant with positive reinforcement via a mobile application, based on his/her sucking on the nipple of the bottle. To achieve this, a Bluetooth enabled pressure sensor and Bluetooth mobile application will need to be developed and tested. Following performance testing in the lab, the device will be beta-tested with volunteering parents and feeding therapists. The team is led by two neonatal intensive care unit (NICU) therapists and researchers who work with premature and term infants to improve feeding skills and promote optimal neurodevelopment and family involvement. Other members of the team include two electrical research engineers at the University of Louisville who specialize in lowpower, wireless sensors and software design. Finally, the last team member is a mobile application developer who is a computer engineer with extensive experience in mobile application and web development."" 08/01/2017 University of Louisville UofL - ExCITE image of external link icon Health IT/Therapeutic Device Sensor to determine infant feeding and corresponding musical app Feeding problems Available
Development of a microfluidic process for long-term preservation of dired red blood cells at ambient temperature Jonathan Kopechek Blood transfusions have saved millions of lives and are the most common medical procedure in the United States. Blood is acquired from donors but in most cases must be used within six weeks. This limitation is responsible for blood shortages that occur in many hospitals and poses a significant barrier to transfusion medicine in places where refrigeration is not available (such as in the field during military operations, or at medical centers in remote locations). Therefore, an effective method to process RBCs for long-term preservation at ambient temperature would have a significant impact. The objective of this project is to develop a device that enables long-term preservation of dried RBCs at ambient temperature by delivering the sugar trehalose into RBCs. Trehalose is a natural occurring cell protectant found in plants and lower animals that helps organisms to survive water-limited states such as dehydration or freezing. However, trehalose does not cross membranes and must be actively loaded into cells that do not naturally express transporters for this sugar. We have recently developed a novel proprietary method for trehalose delivery. Our preliminary studies have demonstrated that this method successfully delivers trehalose to pig and human RBCs and significantly increases cell recovery following freezing/thawing or drying/rehydration. In this project, we will develop a device to improve consistency and precision of trehalose loading into RBCs for increased cell recovery after drying. We will optimize parameters to maximize RBC recovery after drying. In addition, we will characterize the function and structural integrity of the processed RBCs following drying/rehydration by measuring hemoglobin levels, oxygen-carrying capacity, and by microscopically evaluating RBC structure. Finally, we will test dry-preserved and rehydrated RBCs in a rat transfusion model to evaluate safety and efficacy in vivo. These studies will lay the foundation for future testing in large animal models leading to human clinical trials. We have assembled a strong multidisciplinary team, with the knowledge and skills needed to successfully complete this ambitious project. We envision that our product will be used by blood banks and hospitals for long-term preservation of RBCs that are used for blood transfusion in patients (e.g. surgery, cancer treatment, etc.). This product will have a significant impact on human healthcare, and dry-preservation of RBCs could revolutionize civilian and military applications where long-term storage of blood components is currently impossible. 08/01/2017 University of Louisville UofL - ExCITE image of external link icon Combination device and process to preserve dried RBCs Blood storage Available
Leak-free trocar for endoscopic surgery George M. Pantalos ""A trocar (sometimes also referred to as a cannula) is a medical device that a surgeon inserts through the skin that provides surgical instrument access to the operative site during a minimally invasive, endoscopic surgical procedure. A laparoscopy is a surgical procedure in the abdomen and an arthroscopy is an orthopedic endoscopic surgical procedure in a joint capsule (e.g. knee, shoulder); both types of procedures may use several trocars. The problem with trocars is that they leak internally which can cause inconsistent pressure regulation and visualization in the operative site, resulting in adverse events and waste of consumable supplies. We propose the refinement of a leakfree trocar for laparoscopic and arthroscopic procedures. Potential use in other adult and pediatric surgical procedures (e.g. minimally invasive pulmonary artery banding) is being explored. No such device is commercially available for the several million endoscopic surgical procedures conducted in the United States annually. This trocar will provide reliable distension of the operative site while maintaining consistent pressure which will reduce procedure time and patient adverse events as well as reduce the waste of consumable resources (gas/fluid), ultimately reducing costs and minimizing leaked fluid hazard in the operating room. To date, proof-of-concept models of the leak-free trocar, which uses a unique design and arrangement of valves and seals, has been developed and proven to work well enough in bench and fresh tissue (human cadaver) evaluation that a patent application has been submitted to the US Patent and Trademark Office. Several details of design and component optimization are necessary to get to the point where the new trocar has commercialization potential. The goal of the project is to continue design optimization efforts to advance the current model performance, handling, fabrication, and documentation to the level of a product prototype that could be licensed for commercialization to a surgical device company. This will be accomplished by employing unique design and precision fabrication methods available at the University of Louisville followed by performance testing on the bench, in clinically relevant animal experiments, and in fresh human cadavers. Key milestones for this project include the assembly of a Design History File, benchmarking performance of the proposed trocar with predicate trocars in bench, animal, and human cadaver tests, and an educational pre-submission meeting at the FDA Office of Device Evaluation. Failure to achieve leak-free trocar performance during the bench, animal, or human cadaver evaluations constitutes a no-go decision gate. Strengths of the project team include extensive clinical experience with laparoscopic and arthroscopic surgery, extensive medical device development and device evaluation experience, access to excellent facilities at the University of Louisville needed to conduct the project, and three years of prior collaboration on the development and evaluation of the new trocar."" 08/01/2017 University of Louisville UofL - ExCITE image of external link icon Surgical Device Leak-free trocar Endoscopic surgery Available
Predicting and Preventing Acute Kidney Injury Associated with Cardiovascular Diseases Sylvie Breton One third of cardiac surgery patients and 22% of patients with acute myocardial infarction will develop AKI. AKI diagnosis leads to longer hospital stays and worse outcomes. The current marker used for the detection of AKI is serum creatinine (SCr), but SCr is a lagging prognostic marker. The onset of AKI causes no symptoms, and more than 50% of kidney function has already been lost before SCr levels show a detectable rise. AKI has thus been touted a silent killer. If diagnosed quickly and treated early, AKI could be prevented. We have recently identified UDP-glucose (UDP-G) as an early biomarker of AKI in ICU patients. Unlike any other AKI biomarker, UDP-G itself causes injury to the kidneys after release by damaged cells. We have demonstrated through a pilot study that UDP-G in ICU patient urine predicts AKI up to 48 hours before SCr and outperforms other AKI biomarkers. However, currently the only method for UDP-G measurement is cumbersome, and not feasible for use in a clinical lab. This proposal involves the development of the first UDP-G assay, which can be performed with equipment available in a clinical lab. The result of this project will be the prototype used for further development toward an FDA approved test for AKI diagnosis. 11/01/2017 Massachusetts General Hospital B-BIC Small Molecule Drug Acute Kidney Injury Licensed Erin McKenna
Tool for Endobronchial Biopsies of Peripheral Lung Nodules Michael GREMINGER, PhD Lung cancer bioposies in the periphery of the lungs are difficult with standard bronchoscopes are which are too large to access the smaller peripheral lung spaces. The proposed device incorporates ultrasound, video feedback and steerability in an instrument small enough to reach nodules in the lung periphery. 09/01/2017 University of Minnesota MN-REACH Therapeutic device Endobronchial biopsy device Lung cancer Available Kevin Nickels
Development of novel gut-restricted bile acid analogs that inhibit C. difficile infection (CDI) Michael SADOWSKY, PhD The proposed product is a novel drug candidate that inhibits C. difficile spore germination without disrupting the normal microbial community. This bile acid derivative drug is cost efficient relative to biologics and will be used as monotherapy or adjunct therapy to prevent CDI recurrence, or even initial occurrences in care facilities where high numbers of the bacterium are present. 09/01/2017 University of Minnesota MN-REACH Small Molecule Drug Bile acid analogs Clostridium difficile infection Available Kevin Anderson
Preventing Compassion Fatigue in Disaster-Responders: Advancing and Evaluating the Effectiveness of a Mobile Self-care App Tai MENDENHALL, PhD The proposed product is an innovative self-care app for emergency responders in-the-field for targeted attention to compassion fatigue prevention that engages responders in a variety of ways before, during, and after deployments. 02/01/2018 University of Minnesota MN-REACH Health IT mobile app Trauma/Emergency Response Teams Available Andrew Morrow
Midbrain Organoid-Derived Cell Product for Treatment of Parkinson's Disease Timothy O'BRIEN, PhD Current Parkinson's disease therapies are mainly palliative, eventually lose efficacy, and do not prevent disease progression. The proposed cellular therapy provides an effective means for long term treatment of Parkinson's disease by using induced pluripotent stem cells which are easily obtained and do not involve fetal cell sources. 09/01/2017 University of Minnesota MN-REACH Biologic Drug Cell therapy from human midbrain organoids Parkinson's disease Available Raj Upuda
Treatment of Malignant Brain Tumors with the Zika Virus as a Vaccine Adjuvant and Oncolytic Virus Walter LOW, PhD The proposed product is a Zika virus-based immunotherapy and oncolytic therapy to treat patients with glioblastoma multiforme 02/01/2018 University of Minnesota MN-REACH Biologic Drug Zika virus as a vaccine adjuvant and oncolytic virus Glioblastoma multiforme Available Raj Upuda
Oropharynx Appliance to Maintain Airway Patency Dominique Durand, PhD Researchers at Case Western Reserve University are developing and testing a device that restrains the tongue and prevents it from obstructing the airway. This new design can prevent obstruction without causing a gag reflex and still allowing swallowing. The novel technology is an appliance inserted into the mouth and designed to support the tongue during sleep to prevent an occlusion, while still allowing the tongue to move back for swallowing, and preventing gag reflexes during insertion and sleep. The mouth guard is fitted to the lower jaw and precisely fixed to the patients mouth, while the restrainer position is custom-designed for each patient. 01/01/2018 Case Western Reserve University NCAI-CC Device Obstructive Sleep Apnea Available Mark Low
Transcatheter Cardiac De-airing System (TCDS) for Minimally Invasive Cardiac Surgery Jamshid Karimov, MD, PhD Standard air-removal techniques for cardiac surgical procedures are based on techniques that involve manual handling of the heart for gentle massage/compression to mobilize trapped air between chambers. The surgeon uses transesophageal echocardiography (TEE) to visualize air bubbles as they dislodge and dissipate. However, for minimally invasive cardiac surgery (MICS) with small incisions (4-7 cm in length), cardiac manipulation is not feasible. The occurrence of air microemboli in open-heart surgery has been correlated with the degree of post-operative neuropsychological disorders, and must be prevented to improve patients safety. 01/01/2018 Cleveland Clinic NCAI-CC Device Cardiac Surgery Available Mark Low
A Small Molecule Therapeutic for the Treatment of Idiopathic Pulmonary Fibrosis Daniel Lawrence, PhD Plasminogen activator inhibitor-1 (PAI-1) regulates processes such as fibrinolysis and wound healing. However, PAI-1 is also associated with many disease processes, including fibrosis of the lung, kidney, and heart, and may contribute directly to disease progression. Thus, PAI-1inhibition may be an effective approach to treat a wide variety of fibrotic diseases. Prof. Lawrence and his group at University of Michigan have been developing a small molecule inhibitor, CDE-268, which is the only PAI-1 inhibitor that efficiently inhibits PAI-1 bound to vitronectin, the primary form of PAI-1 found in vivo. In addition, CDE-268 is orally bioavailable, has an outstanding pharmacokinetic (PK) profile and a preliminary toxicology study suggests CDE-268 is safe with an estimated therapeutic index in IPF of ~20-fold. Thus, CDE-268 has a significant potential as a therapeutic agent for the treatment of pulmonary fibrosis. 01/01/2018 University of Michigan NCAI-CC Therapeutic Idiopathic Pulmonary Fibrosis Available Vara Prasad Josyula
Novel Augmented and Virtual Reality Application to Improve Surgical Planning in Pediatric Cardiothoracic Procedures Ryan Moore, MD Addressing a gap in current stand-of-care, researchers at CCHMC have developed expertise in creating interactive 3D reconstructions of patient CT/MR data to perform virtual implantations of mechanical circulatory support (MCS) devices in pediatric patients. This 3D virtual surgery simulation has allowed for pre-procedure testing of preferred alternative positions which has led to a successful device placement in pediatric patients that would not have otherwise been possible with current surgical blueprint and simulation tools. Combining a digital surgical blueprint tool with a 3D library of surgical devices, valves, and graft materials will be the first comprehensive procedural planning application available for cardiothoracic procedures. 01/01/2018 Cincinnati Childrens Hospital Medical Center NCAI-CC Tool Cardiac Surgery Available Mark Low
Polarization-Sensitive OCT (PSOCT) Image Guidance for RFA Therapy of Atrial Fibrillation Andrew Rollins, PhD Researchers at Case Western Reserve University are developing a radiofrequency ablation (RFA) catheter with integrated PS-OCT in an intra-cardiac device which can be used for the treatment of AF. The catheter can provide real time, high-resolution, in-depth imaging of the tissue at the catheter tip to guide RFA therapy. This will allow physicians to identify critical substrates and structures to target or avoid, assess catheter-to-tissue apposition, monitor the completeness of a lesion, and avoid complications. Thus, real-time feedback may result in shorter procedure times, lower rates of recurrence, and enhanced patient safety. 01/01/2018 Case Western Reserve University NCAI-CC Device Atrial Fibrillation Available Mark Low
Proximal Hybrid Aortic Stentgraft for Simplified Extended Arch Repair (PHASTER) Eric Roselli, MD The PHASTER technology platform encompasses a novel, simplified endovascualr repair technique and implant for acute proximal dissection, aneurysm or co-arctation. The PHASTER device is a composite of cloth (typically woven polyester or ePTFE) and a self-expanding or balloon-expandable stent (usually nitinol or stainless steel) which is attached to it. The PHASTER device is differentiated by its straightforward, easy to deploy design. Dr. Roselli has proven out the concept of the PHASTER technique in the clinic using modified off-the-shelf devices. 01/01/2018 Cleveland Clinic NCAI-CC Device Endovascular Surgery Available Mark Low
Vortex Catheter Technology for Mechanical Thrombectomy Luis Savastano, MD Researchers at the University of Michigan have developed a high-performance, low-profile device for mechanical thrombectomy based on an augmented hydrodynamic vortex that engages, macerates and removes clots. This technology has shown the potential to enable rapid, complete and un-interrupted removal of large amounts of clot substance that typically cannot be aspirated by large bore catheters. Tests conducted in vascular phantoms of different sizes and geometries have confirmed the efficacy of the macerating mechanism in vasculatures of extreme tortuosity, with minimal risk of intravascular clot fragmentation. This technology has the potential to outperform existing technology in thrombectomy by eliminating the need for multiple delivery systems and multiple thrombectomy attempts. 01/01/2018 University of Michigan NCAI-CC Device Cardiovascular Mechanical Thrombectomy Available Mark Low
A Synthetic Heparin Derivative that Targets Collagen to Repair Damaged Vasculature After Balloon Angioplasty Jason Wertheim, MD, PhD Researchers at Northwestern University developed a heparin molecule that will bind to exposed collagen at the angioplasty site. The therapeutic product being developed is called collagen-binding peptide:Heparin or CBP:Heparin and functions based upon the injury mechanism observed during coronary angioplasty and stent placement. Initial, proof-of-concept studies show specific binding to collagen IV and clot reduction within vasculature and presence of heparin bound to collagen up to one week after administration. Targeting heparin to exposed collagen at the injured vessel may reduce or eliminate the need for repetitive, frequent (daily) doses of systemic anti-platelet agents typically required after PCI. 01/01/2018 Northwestern University NCAI-CC Therapeutic Percutaneous Vascular Intervention Available Vara Prasad Josyula
Targeting Chromatin Dependent Signaling in Heart Failure via Pharmacologic Inhibition of BET Bromodoamain Proteins Saptarsi Haldar, MD 03/01/2015 Case Western Reserve University NCAI-CC Biologic drug Heart Failure Project discontinued
ReHeal Glove Christopher Allan The first Negative Pressure Wound Therapy (NPWT) device/system (KCI VAC) received FDA approval in 1997. Since that time, NPWT has been used extensively for treating open injuries and other wounds, showing great efficacy in accelerating healing and reducing edema and infection risk. Unfortunately, there is no simple or effective NPWT treatment for injuries of the hand. Foam dressings obscure the wound, limit motion, cause painful reinjury upon removal, and (on the hand) can be very difficult to seal. The ReHeal glove is a flexible, textured silicone glove. It is translucent, so wound healing assessments can be made without frequent painful and possibly tissue-damaging dressing changes seen with foam dressings. It permits full range of motion of the hand. The glove is designed to be applied after soft tissue trauma: burns, blast injuries, abrasions, skin avulsions, amputations, post-skin grafting, post-debridement of infections or mangling hand injuries, revascularizations, and even elective surgical wound closure. The glove allows for earlier rehabilitation, resulting in improved functional outcomes for range of motion, grip and pinch strength, sensibility, wound healing and discomfort or pain, thereby increasing patient satisfaction and reducing hospital costs. Our engineering and design needs are well met by our current team. We have developed and pilot-tested a successful prototype, and have DoD funding for a clinical trial. In the present proposal we describe our need for external guidance as we pursue commercialization of the device. The array of consulting and advisory features available within the WE-REACH ecosystem directly address the knowledge and skill gap in our team, and will be crucial to our goal of providing this paradigm-changing medical device to the largest possible number of injured patients who can benefit from the ReHeal Glove. 06/26/2020 University of Washington WE-REACH image of external link icon Therapeutic device Healing from wounds, cuts, abrasions, and traumatic injury Available Teddy Johnson
Power Driven Bone Biopsy Trephine Needle System Clay Larkin With population aging and increasing comorbidity, a growing number of patients develop metabolic bone diseases (MBD) such as osteoporosis and renal osteodystrophy from the associated effects on bone turnover and mineralization. Conditions such as kidney disease, organ transplant, bariatric surgery, cancer, HIV/AIDS, glucocorticoid use and other diseases, result in a significant increase in MBD. Over the past decade, therapeutic options for MBD have expanded rapidly, creating opportunities for targeted treatments. A bone biopsy is the current gold standard for diagnosing the specific type of MBD and facilitates the optimal use of bone-active agents in treatment. It provides information about the mineralized component of bone: turnover, mineralization and microarchitecture. In practice, bone biopsies are performed with trephines that were designed primarily to harvest bone marrow even though both tissues are processed very differently. Qualitative and quantitative histology for a bone biopsy is performed on un-decalcified sections cut from hard resin- or polymer- embedded blocks, preserving the cortical and trabecular microarchitecture. The modern trephines still use a manual technique, and often yield suboptimal bone tissue cores with inadequate preservation of microarchitecture. The manual biopsy technique requires significant training for the operator and is painful to the patient. Power drill modifications, while easier and less painful, yield small cores and produce damage artifacts and debris from an inappropriately designed cutting edge paired with a high-speed drill. These known problems with bone biopsy technology ultimately decrease provider and patient acceptance reducing the accuracy of diagnosis, underscoring the technology gap in meeting the need for appropriate tools. We have designed a dedicated power-driven bone biopsy trephine, compatible with clinical standard power drivers. The device has an optimized cutting edge and luminal design to retain a core suitable for analysis with preservation of cortical and trabecular microarchitecture. The design is currently protected by two provisional patent applications. In collaboration with our industry partner, we seek to translate this design into a working prototype that can be subjected to functional analysis over the first six months of funding. This period will also focus on formal regulatory assessment to identify testing requirements and formulate appropriate strategy. The following six months will refine the prototype using rigorous acceptance criteria and more intensive Feasibility Sample Testing with cadaveric bone samples at the University of Kentucky Bone Diagnostics Lab as our Go/NoGo decision gates. Subsequent product development and refinements will focus on bringing the product to a viable exit strategy over an estimated timeline of 6 to 12 months. Our team consists of a biomedical engineer, clinical experts including nephrologists, bone specialists, orthopedic surgeons, a bone scientist, and an industry partner. We are uniquely qualified to meet the challenges and needs of this project from design inception to clinical output. 07/01/2020 University of Kentucky KYNETIC image of external link icon Diagnostic device Bone disease Available Sarah Andres
Jessica Sharon
A novel anti-IL-6 inhibitor as a new immunotherapeutic for uveitis Howard Donninger Uveitis is an inflammatory disorder of the eye and is the fifth most common cause of blindness. Current therapeutics for uveitis include topical corticosteroids, systemic nonsteroidal anti-inflammatory drugs (NSAIDs), monoclonal antibodies and, in extreme cases, surgery. Not all patients respond to these therapies and all of these options are accompanied by side effects, some of which can be severe and even life threatening. Thus, there remains an unmet need for the development of less toxic therapeutic strategies for uveitis. Targeted therapy may be a more effective option, and one attractive target is IL-6. As an important inflammatory cytokine in the aqueous humor, IL-6 is critical for the differentiation of highly inflammatory Th17 cells which are known to be mediators of uveitis. Antibodies targeting the IL-6 receptor have shown promise in patients with uveitis however, antibodies cannot be delivered directly to the eye and severe toxicity is associated with systemic treatment with these anti-IL-6 biologics. Small molecule inhibitors of IL-6 that can be delivered directly to the eye may prove more effective. We have developed a specific, non-toxic small molecule inhibitor of IL-6 signaling and our preliminary studies show that this inhibitor delays the onset and reduces the severity of uveitis in a preclinical model, and it can be successfully delivered topically to the eye. Optimization and clinical development of this inhibitor may offer an improved and less toxic therapeutic option for uveitis. For this project, we propose to perform additional preclinical studies to confirm that direct delivery of our inhibitor to the eye reduces the symptoms and severity of uveitis and to determine the optimal dosing to achieve maximal activity. Additional studies in year 1 include testing unique, patentable derivatives of our parent compound in vivo, some of which show higher in vitro activity than the parental compound. In year 2, we propose to perform ADME and toxicity analyses on the derivatives that show the highest activity in vivo (limited to the top 3 compounds) and derive a suitable formulation to deliver the inhibitor safely to patients. Upon successful completion of this project, we will have proven that this technology is safe, non-toxic and effective at reducing the symptoms and severity of uveitis when delivered topically to the eye, and thus may be used as a novel immunotherapeutic alone or in combination with existing therapeutic strategies, where it could significantly improve uveitis patient outcome. Our novel compound will be an immunotherapeutic for uveitis and other diseases for which the compound may prove potentially useful, (rheumatoid arthritis, Castlemans disease and certain cancers), where IL-6 plays a major contributing role. 07/01/2020 University of Louisville KYNETIC image of external link icon Small molecule drug Uveitis Available Sarah Andres
Jessica Sharon
A novel target for hepatic lipid accumulation Scott Gordon The common liver condition non-alcoholic fatty liver disease (NAFLD) affects over 25% of the world population and over 30% of the U.S. population. Many of these patients will progress to more severe liver disease. About 20% of NAFLD cases are classified as non-alcoholic steatohepatitis (NASH) which carries significantly increased risk of further progression to cirrhosis or development of hepatocellular carcinoma. These severe conditions can ultimately necessitate liver transplantation 1, 2. It is estimated that NAFLD and associated liver complications cost the U.S. health care system $32 billion per year 3. Little is known about the pathophysiology behind the disease, and there are currently no FDA-approved treatments. The current standard of care for NAFLD patients includes diet and exercise recommendations which, for most, are only modestly effective. Because of the high prevalence, serious medical consequences, and lack of effective treatments there is an extremely large unmet need for NAFLD treatments. My lab has recently discovered a function for the human protein DENND5B. Prior to our discovery, this protein had no known function and virtually no presence in the scientific or medical literature. Our findings, consisting of data from a genetic mouse model (that we generated) and from human gene association studies, indicate a significant role for DENND5B in hepatic lipid metabolism. The primary basis of this proposal is that specific targeting of DENND5B gene expression in the liver may be a viable therapy for NAFLD. In our Dennd5b knockout mouse model, we observe a remarkable resistance to diet-induced lipid accumulation in the liver. Human gene association studies that we have performed in collaboration with investigators at the NIH and the Mayo Clinic have demonstrated that a common DENND5B gene variant is correlated with lower body mass index (BMI) and abdominal circumference 4. In humans, elevated BMI is a risk factor for NAFLD. We have also accumulated additional unpublished data implicating this protein in liver lipid metabolism and protection against fatty liver disease. This gene and its protein product are highly expressed in the liver and represent a novel target of potentially significant clinical interest for the treatment of hepatic lipid accumulation. Our data suggest that reducing the amount of this protein in the liver may provide protection. We propose that targeting of DENND5B gene expression in the liver using an antisense oligonucleotide (ASO) will provide protection and potentially regression of NAFLD. Targeting gene expression using ASO has been utilized in several recently FDA-approved therapies aimed at different target genes and disease conditions 5, 6. The ASO approach has been successfully developed against hepatic targets including one FDA-approved ASO (Mipomersen) targeting hepatic apolipoprotein B expression to treat familial hypercholesterolemia. Phase II trials were just completed for another ASO targeting hepatic apolipoprotein(a) for cardiovascular disease 7, 8. Given the large unmet need of this serious condition, in the past FDA has granted fast track designation for therapeutics targeting NAFLD and NASH which expedites the timeline of the FDA review process 9. The proposal will develop an ASO to knockdown DENND5B gene expression in the liver and will evaluate this compound for therapeutic efficacy and safety in mouse models for NAFLD. 07/01/2020 University of Kentucky KYNETIC image of external link icon Biologic drug Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) Available Sarah Andres
Jessica Sharon
A highly selective mPGES-1 inhibitor as a, effective and non-addictive analgesic Fang Zheng Pain is a significant public health problem costing $560-$635 Billion annually in the US. Opioid is a class of pain medications with the capacity to deliver pain relief, but with high potential for abuse and physical dependence. The other major class of analgesics in clinical use are nonsteroidal anti-inflammatory drugs (NSAIDs) that are non-addictive. However, traditional NSAIDs (including celecoxib, a selective COX-2 inhibitor) have significant cardiovascular, cerebrovascular, and gastrointestinal risks. Interestingly, microsomal prostaglandin E synthase-1 (mPGES-1) is the most promising, ideal target for next-generation NSAIDs, and various mPGES-1 inhibitors have been reported in the literature. Unfortunately, none of the previously reported potent inhibitors of human mPGES-1 have shown to also be potent against mouse/rat mPGES-1, which prevents using well-established wild-type mouse/rat models of inflammation and pain for preclinical efficacy studies. Nevertheless, we have successfully discovered a novel class of potent mPGES-1 inhibitors (including BAR002 as our current lead) that are potent for not only human mPGES-1, but also mouse and rat mPGES-1. BAR002 is also highly selective for mPGES-1 over COX-1/2 and orally bioavailable, enabling preclinical testing using well-established wild-type mouse/rat models of inflammation and pain. Our further in vivo studies have confirmed that, compared to celecoxib, BAR002 is indeed much safer and more effective. In this project, we will test BAR002 and its analogs in various animal models to identify an optimal mPGES-1 inhibitor drug candidate with a suitable oral formulation for safely and effectively treating inflammation and various types of pain. The specific milestones of the proposed entire project: (1) Confirm that BAR002 is a truly promising lead. Go/no-go decision: Go if BAR002 is effective in all the animal models of pain tested. REACH Common Application 2 (2) Perform lead optimization and identify the top-two compounds with their optimal dosing vehicles. Go/no-go decision: Go if top-two compounds (that may include BAR002) along with their optimal dosing vehicles have been identified. (3) Examine the PK/PD profiles and identify the best compound with the optimal oral dosing vehicle. Go/no-go decision: Go if the top compound with an optimal dosing vehicle has been identified and the corresponding PK/PD profile has been determined (4) Determine the maximum tolerated dose (MTD) and minimum effective dose (MED) of the optimal compound with the optimal dosing vehicle in each pain model used. Go/no-go decision: Go if MTD &gt; 3 g/kg and if the MED-associated human equivalent dose (HED) &amp;#8804; 200 mg for all pain models tested. Achieving these milestones will make the optimal mPGES-1 inhibitor ready for subsequent drug development efforts including cGMP (current Good manufacture Practice) manufacturing, IND (Investigational New Drug)-enabling studies, and clinical trials. Our team has extensive experience in rational design, discovery, and development of novel drug candidates, including two tested in Phase II clinical trials. 07/01/2020 University of Kentucky KYNETIC image of external link icon Small molecule drug Chronic Pain Available Sarah Andres
Jessica Sharon
Liposomal azithromycin to reduce cardiac inflammation Vincent Venditto Problem Description: Inflammation is a major cause of secondary injury after a heart attack that results in poor patient prognosis. Uncontrolled inflammation can cause a buildup of scar tissue and thickening of blood vessel walls. Many therapies given after a heart attack (myocardial infarction (MI)), are used to restore blood flow and prevent clotting, but none are designed to target inflammation. There is a need for a potent medication that can be used to limit cardiac inflammatory damage. Intended Customer: Patients presenting to an emergency medical team with an acute MI. Solution: Azithromycin is capable of decreasing inflammation by shifting immune cells to a reparative state. However, the FDA issued a warning for azithromycin due to an increased risk of a fatal irregular heart rate. To address this risk, we have developed a formulation containing azithromycin that reduces cardiac cell death, reduces cardiac scar size, and has decreased off-target toxicity. Liposomal azithromycin (L-AZM) serves as a vehicle for azithromycin to achieve rapid onset of azithromycins immune modulatory function while reducing the off-target toxicity making this a viable treatment option for patients suffering from a MI. Proposed work: The proposed experiments are designed to address three critical aspects of the drug development process: 1) in vitro and in vivo toxicity; 2) timeframe to initiate therapy; and 3) navigating the regulatory pathway. This funding mechanism will support clearly defined objectives that will de-risk the formulation and accelerate continued evaluation of L-AZM toward IND application. Milestones: We propose four milestones evaluating L-AZM: (M1) in vitro toxicity; (M2) in vivo cardiac toxicity in pigs; (M3) therapeutic treatment window; (M4) biodistribution in mice with guidance from a regulatory consultant. Deliverables: The data generated will include in vitro and in vivo toxicity data for L-AZM (M1/2), which stands as the most significant barrier to clinical translation. We will establish the treatment window to initiate therapy in mice (M3) to better identify the target market. Preclinical biodistribution data for L-AZM in consultation with a regulatory consultant (M4) to navigate the drug approval process will also be generated. Team: We are the first team to evaluate L-AZM as a formulation to modulate immune cell function after MI. Our strong preliminary data places our team of experts in a unique position to leverage this finding to advance this formulation into a clinically relevant therapeutic. Our team includes: co-PIs- Vincent J. Venditto, PhD (UK - liposomes), and Ahmed Abdel-Latif, MD, PhD (UK - cardiologist) and a supporting team of collaborators including Dave Feola, PharmD, PhD (UK - macrophages), John Gensel, PhD (UK - macrophages), Brian Delisle, PhD (UK cardiac toxicity), and John M. Canty Jr, MD (U Buffalo - pig model). 07/01/2020 University of Kentucky KYNETIC image of external link icon Small molecule drug Myocardial Infarction, Cardiovascular Disease Available Sarah Andres
Jessica Sharon
Oral, gut-restricted anti-IL-23R therapy for inflammatory bowel disease Stephanie Berger Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut leading to poor quality of life and in severe cases can require bowel resection. IBD represents a $15 billion annual burden in healthcare costs. Standard-of-care antibody therapies are expensive and require inconvenient infusions or injections, leave the patient more susceptible to serious infections due to their systemic immune suppression, and can lose efficacy over time. We have developed computationally designed, hyper-stable miniproteins that represent a completely new mode of treatment for IBD. The miniproteins potently block a well-validated IBD target, IL-23R, can be manufactured in low cost bacterial production strains, and are extremely stable, i.e. resistant to heat, acid and physiological proteases, enabling oral administration. An oral, gut-restricted, anti-IL-23R miniprotein can provide an alternative therapy that is safe, convenient, and cost-effective. With WE-REACH support, we will determine the pharmacokinetics of lead miniproteins after oral administration in rodents, and assess the efficacy of a lead miniprotein compared to a competitor in a rodent model of colitis. With expertise available to us through WE-REACH, we aim to establish a detailed path to IND. 06/26/2020 University of Washington WE-REACH image of external link icon Biologic drug Inflammatory Bowel Disease Available Teddy Johnson
NEDD9 Monoclonal Antibody Therapeutic for Pulmonary Thromboembolic Disease Bradley Maron Increased platelet-endothelial adhesion is a central pathobiological event underlying the pathogenesis of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Current therapies to treat thrombosis in PAH and CTEPH emphasize non-specific coagulation proteins, and are associated with elevated rates of off-target effects (e.g., intracranial hemorrhage). Developing a pulmonary vascular-specific drug has several high impact and favorable advantages to current standard of care, but such therapies not exist currently. In this proposal, we present novel data demonstrating that the substrate domain of the protein NEDD9 is a modifiable target to limit thrombosis selectively in the pulmonary circulation. Specifically, our data suggests that NEDD9 on the outward facing plasma membrane is increased by hypoxia selectively in human pulmonary artery endothelial cells, which, in turn, functions as a target of platelet P-selectin to modulate platelet-endothelial interactions in vitro and pulmonary thrombosis in vivo. We propose experiments using PAH and CTEPH animal models and patient samples to profile the therapeutic effect of a novel monoclonal antibody against the pro-thrombotic NEDD9 peptide sequence (mAb-NEDD9). Go/No-go decisions, pivot points and milestone markers are detailed in the accompanying proposal. Overall, results of the proposed experiments aim to i) establish NEDD9 as a druggable site to inhibit thrombosis in PAH and CTEPH, ii) develop a high quality mAb-NEDD9, and iii) demonstrate that the mAb-NEDD9 inhibits platelet adhesion to pulmonary artery endothelial cells in vitro and inhibits thrombosis, vascular remodeling, and pulmonary hypertension in PAH/CTEPH animal models in vivo. Deliverables from this project will be well positioned for early clinical testing. 02/01/2020 Brigham and Women's Hospital B-BIC image of external link icon Biologic drug Pulmonary Thromboembolic Disease Available
Novel small molecule therapeutics for genetic lung and blood diseases Suneet Agarwal Telomere diseases encompass a spectrum of rare and fatal syndromes that are caused by mutations in genes regulating telomere biology. These include the severe childhood blood disorder dyskeratosis congenita (DC) and later-onset diseases such as pulmonary fibrosis (PF). Despite progress in gene and pathway discovery in telomere diseases in the past two decades, there has been no translation of this knowledge into therapies and there are no curative treatments. In our recent work identifying genetic lesions in DC and PF patients, we defined a new pathway regulating telomere maintenance, which we now aim to target for the treatment of DC, PF and other degenerative disorders. We discovered components of the post-transcriptional machinery that regulate accumulation of the non-coding telomerase RNA (TERC), which is critical for telomerase function and is disrupted in several genetic forms of telomere diseases. We found that inhibiting one of these factors, PAPD5, restores TERC and telomere maintenance in induced pluripotent stem cells (iPSCs) from patients with DC or PF. We have discovered small molecule modulators of this enzyme that we now aim to develop into therapeutics. The goal of this project is to advance a small molecule inhibitor strategy targeting PAPD5 to clinical lead stage. If successful, this strategy will provide a novel approach to manipulate telomerase for the treatment of genetic lung and blood diseases caused by defective telomere maintenance, and potentially other degenerative disorders. 01/01/2020 Boston Children's Hospital B-BIC image of external link icon Small molecule drug treatment of genetic lung and blood diseases caused by defective telomere maintenance Available
Technology for Functional and Metabolic Imaging with Hyperpolarized MRI Aaron Grant MRI provides a wealth of anatomical information, but its ability to assess functional parameters such as blood flow (perfusion) and metabolism is limited by its low sensitivity and the limited range of available contrast agents. This limitation negatively impacts virtually every clinical scenario where contrast- enhanced imaging plays a role, including cancer, heart disease, and stroke, to name a few. In the work proposed here, we hope to build the basis for a new approach to diagnostic imaging based on a technology known as hyperpolarized carbon-13 MRI. In hyperpolarized MRI, a tracer molecule is prepared exogenously in a state of dramatically enhanced nuclear magnetization and administered intravenously, enabling real-time imaging of the transport, uptake, and metabolism the tracer. Molecules including glucose, glutamine, and pyruvate can be imaged with this technology. Applications to heart disease, lung, cancer, diabetes, and inflammation have been demonstrated pre-clinically, and clinical trials in heart disease and cancer are underway. Widespread adoption of hyperpolarization technology has been hampered by the complexity, poor reliability and high cost of existing instruments for preparing hyperpolarized agents. Here we propose to develop alternative technology for hyperpolarization based on simple, inexpensive hardware that employs a method known as parahydrogen-induced polarization (PHIP). As a first step toward development of this technology, in this Pilot application we propose to develop and test a novel myocardial perfusion imaging agent that is tailored for use with parahydrogen-based hyperpolarizers. 02/01/2020 Beth Israel Deaconess Medical Center B-BIC image of external link icon Diagnostic device to assess functional parameters such as blood flow (perfusion) and metabolism Available
PCSK6 Protein as a Therapeutic Agent to Treat Heart Failure Qingyu Wu Heart failure is a life-threatening disease. Natriuretic peptides are cardiac hormones that lower blood pressure and enhance cardiac function. Decreased natriuretic peptide activities are common in heart failure. Recently, we identified proprotein convertase subtilisin/kexin-6 (PCSK6) as the physiological activator of corin, a cardiac protease that activates natriuretic peptides in the heart. In this project, we plan to conduct a pre-clinical study testing our hypothesis that recombinant PCSK6 protein can be used as a therapeutic agent to increase natriuretic peptide activity and improve cardiac function in a mouse model of heart failure. 08/01/2019 Cleveland Clinic NCAI-CC image of external link icon Biologic drug Heart failure Available
A Cloud-Based Decision Support Platform for Precision Dosing in Sickle Cell Disease Russell E. Ware Sickle cell disease is a life-threatening inherited blood disorder affecting millions worldwide. Hydroxyurea is an effective therapy, but optimal dosing requires escalation to the maximum tolerated dose (MTD). As wider access to hydroxyurea treatment is contemplated, the complexity of dose optimization will hinder hydroxyurea uptake, especially for affected children living in low-resource settings. Recently, Drs. Ware and Vinks have developed a novel pharmacokinetics-based model for hydroxyurea dosing, with software algorithms that generate the MTD based on sparse-sampling collection with quantitative hydroxyurea measurement. This PK-guided dosing model is currently in use (TREAT trial, NCT02286154) with robust results to date. We now propose to create an online clinical decision support tool that uses our software algorithm to generate optimal hydroxyurea doses at MTD. Commercialization of this support platform is projected to be substantial, since our tool will eliminate traditional hydroxyurea dose escalation strategies that require time and financial resources including laboratory monitoring. 08/01/2019 Cincinnati Children's Hospital Medical Center NCAI-CC image of external link icon Health information technology Sickle cell disease Available
NanoPlatyx-1, A Biomimetic Nanocluster Product for Stent-Free Management of Restenosis Bowen Wang Drug-eluting stents (DES) are the main-stream management of restenosis (vessel renarrowing) following treatments of cardiovascular diseases, yet serious safety and efficacy concerns have been raised. Recent major debacles in efforts to replace DES highlight the urgent need to identify novel strategies to achieve stent-free delivery of vascular medicines. Our product, NanoPlatyx-1, is designed to achieve intravenously (IV) injectable, stent-free, and targeted anti-restenotic treatment. This product combines the merits of a first-line anti-restenotic drug (Sirolimus), its nanocarrier (an innovative cluster design), and coating with a biomimetic membrane (platelet membrane). As such, NanoPlatyx-1 can potentially eliminate the need of non-replaceable permanent stents and the associated risks. Furthermore, our products IV compatibility enables its application to vessels of all sizes and also a flexible regimen that can be tailored to each patients post-surgery progress and applied in an ambulatory care setting, all deemed as unattainable traits in the era of DES. 08/01/2019 The Ohio State University NCAI-CC image of external link icon Combination product stent-free delivery of vascular medicines Available
A First-In-Class Therapeutic to Block Ischemia/Reperfusion Injury Following Acute William A. Muller Each year, millions of Americans with angina undergo percutaneous coronary intervention (PCI), the standard of care for acute ST wave elevation myocardial infarctions (STEMI) due to coronary occlusions. However, while restoring blood flow and limiting the potential infarct size, reperfusion causes inflammatory damage of its own, destroying healthy tissue and resulting in an infarct much larger and more debilitating than would have resulted without that damage. With more patients surviving acute MI these days, a major new health problem is progression to congestive heart failure (CHF), which is related to infarct size. This project will develop a therapeutic peptide (Tat-KLC1c) to administer along with the standard of care PCI, to selectively block IRI. This will greatly reduce final infarct size, preserving cardiac function, and resulting in fewer arrhythmias and progression to CHF. This adjuvant intervention will also result in fewer re-hospitalizations, decreased overall cost per patient, and a healthier population. 08/01/2019 Northwestern University NCAI-CC image of external link icon Biologic drug ST wave elevation myocardial infarctions (STEMI) due to coronary occlusions Available
tPA nanoconjugate as a thrombolytic agent Vinod Labhasetwar The project focus is on developing the &acirc;tPA nanoconjugate&acirc; as a safe and effective thrombolytic agent to achieve both vascular/tissue protection from ischemia/reperfusion injury while enhancing thrombolytic effect of tissue-type plasminogen activator (tPA). The tPA nanoconjugate would extend the critical time window for treatment with significantly reduced risk of hemorrhage and tissue damage that can have profound impact on morbidity and mortality. The milestones are: 1) Develop a scale-up process for tPA nanoconjugate; 2) Optimize tPA nanoconjugate for on-site easy to use stable formulation; and 3) Evaluate tPA nanoconjugate in dog model of carotid artery embolism. The proof of concept has been demonstrated in rat thromboembolic stroke model following intravenous injection that showed remarkably improved survival with tPA nanoconjugate than with tPA alone (85% vs. 20% at 4 wks). The data from the proposed dog model will accelerate clinical and commercial development of the tPA nanoconjugate for treating embolic conditions. 08/01/2019 Cleveland Clinic NCAI-CC image of external link icon Small molecule drug hemorrhage and tissue damage Available
A Novel Device to Treat Heart Failure with Preserved Ejection Fraction (HFpEF) Barry Kuban, D. The goal of this project is to design, prototype and test the left atrial assist device (LAAD) for the treatment of heart failure patients with preserved ejection fraction (HFpEF). This condition, one of the most common cardiovascular diseases, is associated with high mortality due to the lack of effective treatments. The symptoms of this disease include increased left atrial pressure (LAP) leading to pulmonary edema, decreased end diastolic left ventricular (LV) volume and increased LV stiffness leading to reduced cardiac output. The proposed LAAD is implanted at the mitral position to pump blood from the left atrium to the LV thus reducing LAP and increasing LV end diastolic volume. Since LV contractility is preserved in patients with HFpEF, cardiac output will increase as the LV volume increases. Therefore, the LAAD has the potential to effectively treat the symptoms of a condition for which there are no effective treatments available currently. 08/01/2019 Cleveland Clinic NCAI-CC image of external link icon Therapeutic device heart failure patients with preserved ejection fraction (HFpEF) Available
Autonomous Robotic Oral Appliance for Treatment of Obstructive Sleep Apnea Neeraj Kaplish Undiagnosed obstructive sleep apnea (OSA) affects millions of adults, not only degrading sleep and quality of life, but also increasing the risk of mortality, heart failure, stroke and heart disease. Continuous Positive Airway Pressure (CPAP) is the gold-standard treatment, but 50% of users struggle with adherence. Many OSA patients prefer oral appliance (OA) though cost, lack of insurance coverage and inconvenience of testing presents hurdles to their adoption. We propose a robotic OA that: 1) does not require costly attended sleep studies, 2) avoids expensive fabrication/customization 3) provides improved comfort, and 4) can quantify treatment efficacy. A 10% adoption by diagnosed OSA patients results in a $400M market, however it could be substantially larger should the undiagnosed population being using it to diagnose potential OSA. This project aims to integrate our prior work to realize a clinical grade device and utilize it to perform a human trial to demonstrate efficacy. 08/01/2019 University of Michigan NCAI-CC image of external link icon Therapeutic device Sleep Apnea Available
Novel enzyme therapeutics targeting Alzheimer's disease Ronald Bruntz Fifty million people currently live with Alzheimers Disease (AD) worldwide and this figure is expected to rise to over 152 million by 2050 as the baby-boomer generation ages. The current treatment market, worth over $5 billion, consists of only five FDA approved drugs for AD and each only temporarily improves cognition without modifying the underlying disease pathology. AD research has focused on primarily two proteins as therapeutic targets, beta-amyloid and tau, and R&amp;D efforts have not yielded a new therapy since 2003. Defective glucose metabolism is a clinical hallmark in AD patients. We recently discovered that AD patients develop large glucose aggregates, known as polyglucosan bodies (PGBs), and PGBs are known to drive cognitive impairments and neurodegeneration in other neurological disorders. In collaboration with Valerion Therapeutics, LLC, we developed a novel biologic drug, VAL0417, that degrades these glucose aggregates and has a distinct mechanism from other therapies in clinical pipelines. VAL0417 is an antibodyenzyme fusion that combines a cell targeting domain with an enzyme that degrades PGBs. This fusion provides outstanding cell penetration due to targeting a ubiquitous cell surface protein in the CNS that facilitates the uptake of VAL0417. Our previous work shows that VAL0417 can safely be administered in mice, degrades PGBs of Lafora disease (LD), and improves LD pathology. Here we propose the preclinical assessments needed to validate VAL0417 as an effective AD treatment. We will first demonstrate that VAL0417 degrades AD-PGBs in vivo. Next, we will define the impact of VAL0417 on AD-associated neurodegeneration and also perform metabolomic analyses to identify surrogate endpoints or features to detect responses to therapy. Finally, we will assess VAL0417 for improvements in memory-associated behavioral assays in rodent AD models. We filed a method-of-use provisional patent (#62/987,208) for the use of VAL0417 in AD. Valerion and other companies have expressed interest in licensing use through us and supporting the translational effort to test efficacy in AD patients and then into clinical trials. Our team has extensive experience with diseases related to PGBs and has unique expertise to perform the work outlined in this proposal. We expect to show that by degrading AD-PGBs, VAL0417 will slow neurodegeneration and improve cognition in AD models and will generate the preclinical data needed to move the technology into commercial partnerships. 07/01/2020 University of Kentucky KYNETIC image of external link icon Biologic drug Alzheimer's Disease Available Sarah Andres
Jessica Sharon
Development of a Differential Scanning Calorimetry System for Rapid Identification and Differentiation of Specific Causes of Heart Damage Including Different Types of Myocardial Infarction Thomas Roussel Each year ~ 6 million patients in the U.S. present to the hospital with chest pain suggesting myocardial infarction (MI), but only 30% are in fact experiencing a problem requiring medical attention. The remaining 70% are discharged with a benign diagnosis at a cost of approximately $10 billion/yr. Despite the expense, studies have demonstrated that 25% of patients discharged home with a benign diagnosis have experienced an acute MI on follow-up. Delay in diagnosis leads to a delay in treatment, resulting in a worse prognosis compared to those correctly diagnosed on the initial encounter. Limitations in efficiently diagnosing or ruling out an acute MI are due to inadequate diagnostic tools. All available non-invasive diagnostics (e.g., troponin, ECG) detect heart damage (myocardial injury), not the underlying cause (the desired therapeutic target) of the myocardial damage. While current guidelines distinguish between thrombotic (Type 1) and acute non-thrombotic myocardial injury (Type 2 MI, acute non-ischemic myocardial injury), clinically actionable criteria to distinguish between each MI type do not exist. Our focus is development of a point-of care acute clinical DSC device for the real-time diagnosis of MI. We propose to develop a microelectromechanical systems (MEMS)-based thermal analysis sensor (M1: go/no-go is confirmation of suitable agreement of our sensor vs. commercial DSC) with a temperature isolated sample enclosure (M2: go/no-go is sample enclosures with adequate thermal isolation and intimate sensor-sample contact during heating) and control platform that incorporates sensor control and data extraction (M3: go/no-go is performance similar to commercial DSC platform), with evaluation using selected protein standards and MI/control samples (M4: go/no-go is suitable agreement in thermogram profiles between our sensor and commercial DSC). At the end of this project, we will have developed and verified a first generation MEMS-based DSC sensor with similar performance compared to expensive, slow commercial benchtop DSC. A point-of-care blood test that differentiates between different types of myocardial injury, e.g., different types of acute MI, would result in fewer procedures for the patients, patient specific treatment (precision medicine), decreased hospital time (e.g. increased patient turnover), and reduced costs. This project will be led by Drs. Roussel, DeFilippis and Garbett who have fused their respective expertise in DSC, microfluidics/sensors and cardiology over the past three years and generated preliminary data that shows distinct differences in DSC profiles between patients with acute thrombotic MI, acute non-thrombotic myocardial injury, and stable coronary artery disease, a critical distinction for the most effective diagnosis and treatment of MI patients. This project will result in a commercializable miniaturized DSC sensor that discriminates between acute MI patients, the foundation of a promising point-of-care DSC system for the rapid identification of acute MI. 07/01/2020 University of Louisville KYNETIC image of external link icon Diagnostic device myocardial infarction Available Sarah Andres
Jessica Sharon
Radioactive Scandium Complexes to Image Prostate Cancer with Positron Emission Tomography Eszter Boros 220,800 new cases of prostate cancer are diagnosed every year. Routine prostate cancer screening includes a digital rectal exam of the prostate with assessment of prostate-specific antigen (PSA) levels in the blood. Elevated PSA levels merit further assessment of the prostate by intra-rectal biopsy to eliminate a very large percentage of false positives. Current diagnostic tools are inadequate for unambiguous, non-invasive and rapid identification of the disease. The long-term objective of this proposal is to develop a non-invasive imaging tool to enable rapid diagnosis to inform and monitor treatment planning using positron emission tomography (PET). The trans-membrane peptidase prostate-specific membrane antigen (PSMA) is highly expressed in poorly differentiated, metastatic, and hormone-refractory adenocarcinomas. Thus, PSMA represents an attractive target for imaging and therapy. One nuclear imaging tool targeting PSMA is FDA approved: ProstaScint, an antibody-based SPECT tracer. 18F-DCFPyL, a promising small-molecular PET tracer is currently in phase III clinical trials. Both imaging tools exhibit significant shortcomings: poor pharmacokinetics and target accumulation (ProstaScint) or dependency to a cyclotron production facility (18F-DCFPyL) in close proximity and lack of corresponding chemically equivalent, radiotherapeutic tools. 44Scandium has recently emerged as an attractive, short-lived, generator-produced PET isotope with a matched radiotherapeutic isotope for &Icirc;&sup2;- therapy (47Sc). In this feasibility proposal, we will explore the radiolabeling with 44Sc of new chemical entities with high affinity to PSMA. Subsequently, the accumulation of these 44Sc-labeled PSMA targeting small molecules will be quantified via PET imaging and post-mortem biodistribution studies in a pre-clinical small animal model of prostate cancer. 03/16/2018 Stony Brook University LIBH image of external link icon Diagnostic device Imaging technique Available
Enhancement of Protein Yields Using Mechanical Signals: Augmenting Biotech Production to Reduce Drug Costs Meilin Ete Chan "Bioprocessing techniques have profoundly advanced biopharmaceutical efficacy and availability for novel drug development and regenerative medicine applications, generating a multi-billion dollar industry. The resources necessary to distill cellular products which ultimately address heavy market demands, however, are costly and the processes, cumbersome, presenting a significant manufacturing bottleneck. Chemical and media-derived solutions can hinder persistence of cellular output preventing adequate yield in a burgeoning market. Predicated on established translational research demonstrating that low intensity vibrations (LIV), a sub-gravitational (&lt;1g-acceleration), high- frequency (1-100Hz) mechanical signal stimulates a cellular response, this application proposes the use of low intensity mechanical signals as a novel strategy to overcome these limitation in bioprocessing. Our objectives in performing these aims are to alter, but ultimately increase, the rate of proliferation and production of exogenous and endogenous proteins sought by industry, such as recombinant-insulin in CHO cells by optimizing signal and temporal parameters to administer LIV. Our commercialization strategy will expand the range of LIV technology towards new in vitro applications, generating a foundation for future development of viable devices or for incorporation into existing incubation/culture facilities. Intellectual property will be developed around these optimized parameters, incorporating refractory (rest) periods between administrations in order to improve titer and protein yield on an industrial scale. 03/16/2018 Stony Brook University LIBH image of external link icon Other Bioprocessing Available
Chimerica Antigen Recognizing Bacteria to Treat Cancer Yue Zhang "Last few years witnessed the remarkable achievement of CAR T-cells in cancer treatment. However, immunotherapy using CAR T-cells utilizes patients&acirc; own T cells, which are not always available from elderly or immunocompromised patients. Here I propose to use chimeric antigen recognizing (CAR) bacteria to replace CAR T cells to treat cancer. The initial goal is to cure the elderly patients with Diffuse Large B-cell Lymphoma, an aggressive form of B-cell lymphoma that strikes more frequently the elderly. CAR bacteria will be constructed from an attenuated gram negative bacterium, which injects toxic proteins into cells after its adhesins bind to cell surface proteins. For the feasibility studies proposed here, the CAR bacteria will be constructed and optimized. Obtaining a CAR strain that injects proteins specifically into cells bearing the antigens will be a milestone, and will pave the way to future research to further modify the CAR bacteria to be safe for all patients and to be able to kill cancer cells efficiently. With extensive expertise in pathogenesis of our gram negative bacterium, I have confidence in accomplishing the proposed work in a timely manner. 03/01/2019 Stony Brook University LIBH image of external link icon Biologic drug Diffuse Large B-cell lymphoma Available
A Novel Recombinant BCG-Based Immunotherapy Platform for the Treatment of Cancer Jessica Seeliger "Patients with advanced or metastatic bladder cancer disease have a dismal prognosis and few treatment options after first-line chemotherapy. More recently, therapy with immune checkpoint inhibitor antibodies has shown durable clinical responses in bladder cancer, but the reported response rates warrant improvement. BCG is a non-pathogenic attenuated strain of Mycobacterium bovis that stimulates diverse innate and anti-bacterial adaptive immune responses and is a well known non-specific immune stimulant with an extensive clinical safety record as both a tuberculosis vaccine and a cancer therapeutic. The overall goal of this proposal is to construct proprietary immunotherapy agents based on BCG genetically engineered to stably express and secrete tumor neoantigens and an immuno- stimulatory factor for the treatment of advanced/metastatic bladder cancer. Candidate strains that display the highest levels of expression and secretion will be further prioritized based on their ability to stimulate immune responses in cellular assays. The team has experience in mycobacterial genetics, biochemistry and immuno-oncology necessary to meet the proposed goals. We expect to identify lead candidates that meet feasibility criteria and can proceed to the in vivo evaluation of anti-tumor activity in the next stage of development." 03/19/2018 Stony Brook University LIBH image of external link icon Other Feasibility Available
Generation of a Novel Therapeutic Antibody for Treatment of Allergic Asthma Steven Greenberg Asthma affects 8% of the US population, approximately 25 million people. About 10% of patients have severe asthma, accounting for an estimated 1.8 million emergency department visits, 439,000 hospitalizations, and 3,630 deaths annually in the US [1]. Airway inflammation in asthma can be classified as either eosinophilic or non-eosinophilic. Eosinophilic asthma is driven by Th2 mechanisms sustained by innate lymphoid cells type 2 (ILC2) and pathogenic effector Th2 (pETh2) cells&acirc; production of interleukin 5 (IL-5), leading to bronchial eosinophilia. Non-eosinophilic asthma is less well understood but Th17 pathways are a major contributor, responsible for neutrophilic infiltration of the airways [2]. The proposed technology is designed to treat both eosinophilic and non-eosinophilic asthma via a therapeutic monoclonal antibody (mAb) designed to work via targeting depletion of innate lymphoid cells type 2 (ILC2), pathogenic effector Th2 (pETh2) cells, and Th17 cells. 08/01/2019 Brigham and Women's Hospital B-BIC image of external link icon Biologic drug Allergic Asthma Available
Humanized anti-DEspR antibody therapy for acute respiratory distress syndrome Nelson Ruiz-Opazo Acute respiratory distress syndrome (ARDS) and its progression to multi-organ failure (MOF) affects ~200,000 ICU patients each year in the US, with high mortality and healthcare costs. ARDS is driven by hyperinflammation-injury cycles that begin as a normal injury response but become dysregulated causing secondary-tissue injury in the lung and other vital organs, culminating in MOF and death. An actionable key culprit that drives secondary-tissue injury is the activated neutrophil that continually releases bacterio/cyto-toxic enzymes. To date, there is no pharmacotherapy to stop neutrophil-driven secondary-tissue injury in ARDS-MOF. DEspR (Dual Endothelin-1/signal peptide Receptor) is a receptor for endothelin-1 and VEGF-signal peptide expressed by activated neutrophils as a survival factor that allows them to escape apoptosis and perpetuate vicious cycles of secondary-tissue injury in ARDS. Our B-BIC Pilot project provided proof-of-concept data that ABTM-468, a humanized-IgG4[S228P] anti-DEspR antibody, reduces the survival of an activated-neutrophil subset associated with poor outcomes, and reduced downstream components of a vicious cycle. Thus, ABTM468 may stop hyper-inflammatory vicious cycles in ARDS. In this DRIVE proposal, we aim to advance the testing of ABTM-468 efficacy ex vivo in ARDS patient blood samples to confirm and extend the Pilot efficacy data (Aim 1), identify biomarkers of responders and surrogate markers of early response and toxicity (Aim 2), and test for involvement in lung injury from the epithelial side (Aim 3). These data will provide a solid foundation for the clinical development of ABTM-468 in ARDS. 09/01/2019 Boston University B-BIC image of external link icon Biologic drug Acute Respiratory Distress Option to license
Novel Molecules with Cancer-Selective Cytotoxicity Craig Grapperhaus The proposal by Grapperhaus (PI) and Buchanan (Co-PI) seeks to develop a small library of copper complexes into a potential new cancer drug through the collaboration of chemists, microbiologists and medical school scientists. Current cancer treatments methods are often inadequate as about 35% of those with cancer die as a result, usually within 5 years of diagnosis. Furthermore, a lack of selectivity for cancer cells vs. healthy cells often leads to serious side effects. New agents that are more effective at killing aggressive cancer cells while sparing healthy cells are urgently needed. Since the discovery and wide-spread clinical use of cisplatin and its derivatives, there has been considerable interest in the development of new cytotoxic metallodrugs capable of selectively targeting cancer cells over normal cells. The novel Cu(II) complexes prepared by the PI and Co-PI display potent and selective anticancer activity. Notably, they also display potent activity against solid tumor cells and operate via a novel mechanism of action. A clear understanding of mechanism of action is highly advantageous in drug development and defining the molecular target(s) of experimental cancer drugs may be essential for clinical success. Through the proposed work, we seek to identify the mechanism of action, evaluate the structure activity relationship and improve solubility, and evaluate toxicity of these complexes. 08/01/2019 University of Louisville UofL - ExCITE image of external link icon Small molecule drug cancer Available
Specific Medication Use Risk Evaluator for Individuals: A support tool for providers and consumers Demetra Antimisiaris The product estimates risk of using a medication for an individual person. For example, if you have breast cancer, your oncologist can treat you with either Tamoxifen or Anastrozole. Both have the same efficacy in preventing recurrence of breast cancer. But each has different risks. Tamoxifen&acirc;s significant risks are thrombi (heart attack, DVT, pulmonary embolism, stroke) and uterine malignancy. Anastrozole&acirc;s significant risks include high cholesterol, fractures and osteoporosis, increased risk of ischemic cardiovascular events (thrombi essentially). Since the risks for these efficacy equivalent choices for treatment are slightly different between agents, this software can help the clinician with risk assessment for the individual patient, to select the agent with the least risk of use, since each patient has individual risk factors. This clinical tool can help prescribers assess medication use risk before and during prescription of a medication. It can assess concurrent disease risk, frailty risk, unmitigated risks (untreated hypertension vs treated for example as a risk for thrombi), and help the prescriber consider risks they may not be aware of. Therefore, this tool can be used for both pre prescription risk awareness as well as monitoring of mediation use longitudinally. It can be used by hand population of risk factors or auto population from EHRs. Currently, this method has been piloted on one medication, but the aim is to work with Edj Analytics to submit an STTR or identify product development investors based on development of a prototype. There is an RDF on file with U of L OTT. 08/01/2019 University of Louisville UofL - ExCITE image of external link icon Health information technology Pharmacy Available
Vertify Probe: a device for intraoperative measurement and interpretation of bone strength during spinal surgery Maxwell Boakye "Over 50 million Americans have osteoporosis. With the growing elderly population an increasing number of spine surgeries are performed in osteoporotic patients. Complications after spinal surgery are more numerous and of greater severity in osteoporotic patients with much higher health resource consumption and poor quality of life for patients. Many spinal instrumentation complications can be avoided if the surgeon is aware that the patient is osteoporotic and employs evidence-based strategies to alter their surgical technique and mitigate the risk of failure. Preoperative DEXA scans for diagnosing osteoporosis are not always available, cannot be used in the operative room and when available does not measure bone quality at the site of interest. There is an unmet clinical need to know a patient&acirc;s bone density intraoperatively very specifically at the site of interaction between the instrumentation and the skeleton. Our goal is to design a device that is inserted into the bone that measures bone quality at multiple levels within the vertebrae, specifically where the screws or other instrumentation will be placed. In addition to the measuring bone density intraoperatively during spine surgery it will be linked to software that lights up (red, yellow or green) depending on the severity of the measurement and provides surgeon with guidance to management of low-density measurements. A preliminary search shows no such devices are commercially available and large size of the spinal instrumentation market provides an opportunity to create a patentable device to fill this unmet need. 08/01/2019 University of Louisville UofL - ExCITE image of external link icon Diagnostic device Orthopedic/neurology Available
Treasure Trunk: An Interactive Therapeutic Tool, Disguised as a Game, to Enhance Postural Control in Children with Neuromotor Deficits Andrea Behrman Many children with spinal cord injury (SCI) and many with cerebral palsy (CP) cannot sit upright on their own due to paralyzed or weak trunk muscles. They rely on support through their arms or seating and braces to hold them up. Impaired sitting limits a child&acirc;s ability to play and to use their hands. These children are at a high risk for developing scoliosis (a stiff curve of the spine), pneumonia, and pressures sores, and often require surgery. Only recently have two therapies, activity-based locomotor training and targeted training, resulted in improved trunk control in these children. While promising, both therapies require intense practice. Therapists often repeat to the child, &acirc;Keep your shoulders back&acirc;, again and again. Such verbal cueing often becomes monotonous with diminished return. Alternatively, play is a most motivating activity for children and play that &acirc;rewards&acirc; behavior, such as keeping your shoulders back, results in greater repetition. The objective of this proposal is to develop a prototype, Treasure Trunk, an interactive game, as a therapeutic adjunct to engage children to maintain an upright trunk while sensing the child&acirc;s trunk position during intensive and challenging therapies. To the child, this tool will appear as a game with story, goals, rules, obstacles, and rewards, yet interfaces with the child via sensors responsive to trunk position. Our collaborative team will develop a prototype game to increase a child&acirc;s time sitting up on his/her own and accelerate the impact of therapy on a child&acirc;s ability to sit upright. 08/01/2019 University of Louisville UofL - ExCITE image of external link icon Health information technology Neuromotor deficits Available
Point-of-Care Blood Assay Using Differential Scanning Calorimetry to Diagnose Acute Myocardial Infarction Thomas Roussel More than eight million Americans present to emergency rooms with chest pain while only 760,000 of these patients are experiencing acute myocardial infarction (MI). The gold standard to diagnose MI is an assay to measure slowly increasing troponin levels in the blood. However, this test cannot differentiate between Type 1 (thrombotic) and Type 2 (non-thrombotic) MI. Differential scanning calorimetry (DSC) is an analytical technique that measures the thermal profile of biomolecules that may provide a potential method for accurate MI diagnosis. Preliminary studies have shown that thermograms were distinct among stable coronary artery disease, Type 1 and Type 2 MI subjects at acute presentation and similar at quiescent state. However, the development of DSC as a clinical tool has been hampered by the need for specialized training, expensive instrumentation, and notoriously low sample throughput. The objective of this proposal is to develop a chip-based DSC with a disposable sample preparation module to enable rapid data collection and processing, substantially increasing the ability to analyze a larger quantity of samples. The technology developed in this project will be evaluated with DSC standards and compared to conventional DSC instrumentation. The proposed work overcomes the limitations of current DSC instrumentation to enable the transformation of DSC into a point-of-care blood diagnostic assay to provide rapid, inclinic testing. The proposed platform will provide a sensitive and cost-effective analysis with the potential to provide a rapid and portable diagnostic aid for MI. 08/01/2019 University of Louisville UofL - ExCITE image of external link icon Diagnostic device Myocardial infarction Available
Developing Q-Griffithsin as a new antifungal agent Henry Nabeta The global prevalence of recurrent vulvovaginal candidiasis (RVVC) infection is estimated at 6% of all women annually. RVVC and infection with human immunodeficiency virus (HIV) are associated with resistance to anti-fungal drugs. The projected economic burden from lost productivity due to RVVC by 2030 is US$14.39 billion. Candida isolates have also been found in rectal specimens and swabs in men who presented with anal itch and discharge disease. However, there is still scanty data available about rectal candidiasis. We have obtained a &acirc;Study May Proceed&acirc; approval from FDA for Griffithsin M78Q&acirc;s (Q-GRFT) use in the first-in-human clinical trial as a rectal microbicide against HIV infection. We have shown in vitro that Q-GRFT binds to and inhibits the growth of C. albicans. Our goal is to develop Q-GRFT as an anti-fungal agent for use against vaginal and rectal candidiasis. The shorter pathway to getting the product in clinic is to develop it as a rectal product, given existing GLP rectal toxicology and the imminent first-in-humans clinical trial with a rectal enema. There are more patients with RVVC, but this pathway will be longer, given the paucity of vaginal GLP toxicity data. Findings from planned in vitro and in vivo experiments will provide the necessary information required for further exploration of Q-GRFT&acirc;s use as an anti-fungal drug in a human clinical trial setting. 08/01/2019 University of Louisville UofL - ExCITE image of external link icon Biologic drug Antifungal Available
Magnetic Resonance Elastography Derived Stiffness: A Novel Biomarker in Diagnosing Pulmonary Fibrosis Arunark Kolipaka Lung disease is the third leading cause of death (~7%) worldwide and produces an economic burden of $154 billion/year. Currently, there is no noninvasive technique to estimate mechanical properties of the lungs, which would provide both location and extent of the disease for proper diagnosis and treatment planning. Magnetic Resonance Elastography (MRE) is a noninvasive technique to estimate spatial stiffness of lungs without use of any radiation or contrast agent. This proposal aims to develop a commercial product to obtain spatial stiffness maps of the lungs that can potentially provide valuable information for early diagnosis and treatment of IPF to reverse the disease conditions if treated early and improve the life expectancy. The product includes a software package (i.e. MRE sequence and inversion algorithm) that produces robust spatial stiffness maps even in the presence of very low signal&acirc;to-noise such as in MRI of lungs. 01/01/2019 Ohio State University NCAI-CC image of external link icon Diagnostic device lung disease Available
UH Insights Blood &amp; Transfusion Management Support System James Hill Blood transfusions carry risks of negative outcomes and often contribute to lengthened hospital stays. Evidence is increasingly indicating that a large fraction of transfusions may be unnecessary, thereby introducing unnecessary complications and costs. This evidence, along with the rising price of blood products, has incentivized hospital systems to understand exactly how blood products are being utilized and to change the behavior of providers who are over-transfusing. UH Insights determines the appropriateness of blood transfusions by providing customized control processes that improves outcomes, lowers costs, and optimizes resources. The system not only provides an in-depth measures and benchmarks, but also offers actionable strategies to change provider&acirc;s' behaviors. The proposed project will de-risk the platform by validating, optimizing, and enabling the rollout of UH Insights to a new site, while also laying the ground work to implement decision support capabilities at the time a transfusion is considered. 01/01/2019 NCAI-CC image of external link icon Health information technology blood transfusion Available
Small Molecule Therapeutics for the Potential Treatment of Heart Failure Stanley Hazen Our investigative team discovered a link between gut microbiota and cardiovascular disease (CVD) (Wang et al, Nature, 2011). Specifically, we observed trimethylamine-NOxide (TMAO), an obligatory product of gut microbiota metabolism of dietary nutrients abundant in a Western diet (choline, lecithin, carnitine) is linked to CVD risks including heart failure (HF) in multiple patient populations (Koeth et al, Nature Medicine, 2013; Tang et al, NEJM, 2013). We also showed TMAO promotes atherosclerosis, thrombosis and adverse ventricular remodeling in animal studies of HF. After initial proof of concept development of a non-lethal microbial choline trimethylamine (TMA) lyase inhibitor (Wang et al, Cell, 2015), we more recently developed and characterized a family of next-generation, mechanism-based suicide substrate inhibitors that potently target gut microbial production of TMA, the precursor of TMAO (Roberts et al, 2018, Nature Medicine). We have designed, synthesized, and tested several hundred molecules that target microbial TMA generation, and many display potent inhibition (nanomolar to picomolar EC50) in vitro, and efficacy in murine models of disease, with no observable toxicity. Our next step is lead maturation and identification of a candidate with optimized in vivo efficacy and pharmacological properties to take forward on IND enabling studies. 01/01/2019 Cleveland Clinic NCAI-CC image of external link icon Small molecule drug CVD Available
Serum Biomarkers of Pulmonary Fibrosis Induction, Progression and Resolution William Hardie Idiopathic pulmonary fibrosis (IPF) remains a significant cause of morbidity and mortality worldwide. As pulmonary fibrosis is often a progressive but insidious process, a significant challenge is identifying reliable and rapid markers of drug efficacy. The goal of our proposal is to validate serum biomarkers which can be used for the diagnosis and management of IPF. Using a well characterized cohort of IPF patients studied longitudinally we have incorporated measurements of 23 unique serum biomarkers to develop a novel clinical outcome measure that can be used to assist with the diagnosis and assess clinical progression in IPF. This project leverages our teams&acirc; expertise in mass spectrometry, biostatistics, mouse lung fibrosis models, and biomedical commercialization. The team is uniquely positioned to deliver commercially viable, high-value diagnostic and prognostic tests for IPF for use in clinical care settings and companion diagnostics for future clinical trials. 01/01/2019 Cincinnati Children's Hospital Medical Center NCAI-CC image of external link icon Diagnostic assay Idiopathic pulmonary fibrosis (IPF) Available
Harmonic Balloon Angioplasty &acirc; Plaque-Buster &acirc; Improved Treatment for Peripheral Artery Calcifications Hitinder Gurm Plaque-Buster is a device developed at the University of Michigan to improve the treatment of calcified, atherosclerotic plaques in cardiovascular peripheral arteries. Treatment of calcified plaque in peripheral arteries represents over a third of the approximately 700,000 peripheral artery plaque treatment cases per year in the United States. Current treatment methods such as static balloon angioplasty and atherectomy have led to poor outcomes and safety issues. To improve the treatment of calcified plaque, Plaque-Buster incorporates a proprietary, patent-pending oscillatory pressure control mechanism into the conventional balloon angioplasty device and procedure. A functioning prototype of the Plaque-Buster device has been developed by the team and has shown initial success in proof-of-concept testing. The goal of this NCAI-CC grant proposal is to continue Plaque-Buster development and to demonstrate its safety and efficacy compared to conventional treatments. The proposed research plan will consist of three milestones: (1) component and frequency control development and packaging, (2) injury comparison in healthy animal iliac arteries treated with HBA and BA, and (3) comparison of calcified ex-vivo arteries treated with HBA and BA. Each of the proposed milestones fits into our overall commercialization strategy, which includes licensing of the device to potential strategic partners. These partners have confirmed the proposed testing as necessary milestones required for a successful exit. 01/01/2019 University of Michigan NCAI-CC image of external link icon Therapeutic device treatment of calcified, atherosclerotic plaques in cardiovascular peripheral arteries Available
A novel suction tip sleeve to facilitate laparoscopic surgery Aurora Pryor "Aspiration of fluid is an integral step in most laparoscopic procedures. This process can be impaired if tissue is aspirated along with fluid, effectively clogging the suction device and compromising patient safety. We have designed a novel suction tip sleeve that works in conjunction with a commonly and commercially available laparoscopic suction irrigation system that can improve visualization and irrigation of the operative field. The suction tip sleeve will be a disposable, non-implantable medical device. The research plan plan will include the development of detailed CAD drawings of multiple sleeve embodiments based upon the current OTLIR Disclosure, each version of the drawing to be iteratively reviewed by a focus-group of practicing surgeons at Stony Brook. A professionally engineered prototype of the most promising sleeve embodiment (as determined by a small group of Stony Brook surgeons) will be chosen for prototyping. The prototype will then undergo rigorous pre-clinical bench-top testing to evaluate functionality, with iterative improvements made to address deficiencies. Strategies to mitigate future regulatory and manufacturability risks (i.e. use of plastics with known FDA material master files, known medical functionality and commercially acceptable costs) will be utilized throughout the entire process development. 03/01/2019 Stony Brook University LIBH image of external link icon Therapeutic device Surgery Available
Developing a non-invasive diagnostic for endometriosis Christine Metz Endometriosis, characterized by the growth of endometrial-like tissue outside of theuterus, affects 1 in 10 women of reproductive age.1-3Endometriosis is most commonly accompanied bypelvic pain and dysmenorrhea.1, 3-5The diagnosis of endometriosis requires surgery and typically takes 6-10 years.6-8Delayed diagnosis (and treatment) leads to reduced productivity and infertility, inflating itsfinancial burden.7, 9In addition, the social and psychological impacts of endometriosis are considerable.7, 10, 11Clearly, a rapid and noninvasive diagnostic test for endometriosis would fill a large unmet medical need. We propose to develop a rapid non-invasive diagnostic for endometriosis using menstrual effluent(ME). Our published studies demonstrate that ME collected fromendometriosis patients is distinctly different from ME from healthy controls.12This approach is supported by additional observations. Spontaneous endometriosis occurs only in menstruating women, non-human primates, and bats;non-menstruating animals don&acirc;tdevelop endometriosis13-15and itcan be induced by injecting endometrial tissues into the pelvic cavities of recipient baboons.14, 16Furthermore, Sampson&acirc;s theory of retrograde menstruation invokes the reflux of shed MEinto the peritoneal cavity in a causative role.15, 17, 18Therefore, we propose to test the feasibility of using ME to develop a diagnostic forendometriosis. 03/01/2019 Feinstein LIBH image of external link icon Other Endometriosis Available
Patient Specific Target Mapping for Treatment of Atrial Fibrillation Jayakumar Sahadevan We are developing the Arrhythmia I-Spy system to impact clinical outcomes for patients with persistent and long standing persistent atrial fibrillation (AF). To accomplish this, the two component system offers what is not yet available in the market; an AF target software able to identify drivers of AF giving physicians a clear ablation target. This AF target software works in combination with our multi-electrode, high density mapping catheter that was funded through NCAI (2017) and successfully completed. This proposal is for the transformation of the AF target (driver detection) software from a research tool into a commercially viable product. The AF software and design of the multi-electrode mapping catheter is a translational product from our decades of research and published data identifying the existence of AF sources in patients with persistent and permanent AF. 01/01/2019 Case Western Reserve University NCAI-CC image of external link icon Diagnostic device persistent and long standing persistent atrial fibrillation (AF) Available
Non-invasive Diagnosis of Pancreatic Cancer Arie Kaufman Virtual Pancreatography (VP) is a system for the analysis of benign and malignant pancreatic cysts in DICOM images acquired from radiological scanners. Specifically, VP provides a set of tools to perform a user-guided or automatic segmentation of the pancreas glans and pancreatic cysts, automatic histopathological classification of the segmented pancreatic cysts and 3D visualization tool. VP is a non-invasive diagnostic device intended for use in the diagnostic evaluation by a physician of patients with potential or confirmed pancreatic cysts. 03/01/2019 Stony Brook University LIBH image of external link icon Diagnostic device Pancreatic Cancer Diagnosis Available
Enhancement of Protein Yields and Cell Proliferation Using Mechanical Signals: Augmenting Biotech Production to Reduce Drug and Cellular Therapy Costs M. Ete Chan Bioprocessing techniques have profoundly advanced biopharmaceutical efficacy and availability for novel drug development, regenerative medicine, and cellular therapy for cancer treatment, generating a multi-billion dollar industry. The resources necessary to distill cellular products which ultimately address heavy market demands, however, are costly and the processes, cumbersome, presenting a significant manufacturing bottleneck. Chemical and media-derived solutions can hinder persistence of cellular output preventing adequate yield in a burgeoning market. Predicated on established translational research demonstrating that low intensity vibrations (LIV), stimulates a cellular response, this application proposes the use of LIV as a novel strategy to overcome these limitation in bioprocessing. Our objectives are to alter, but ultimately increase, the yields required by various bio-manufacturing processes. Our commercialization strategy will expand the range of LIV technology towards new in vitro applications, generating a foundation for future development of viable devices or for incorporation into existing incubation/culture facilities. 03/01/2019 Stony Brook University LIBH image of external link icon Other Bioprocessing Available
Diagnostic for Acute Kidney Injury Associated with Cardiovascular Diseases Sylvie Breton Acute kidney injury (AKI) is a frequent complication in hospitalized patients, including those undergoing cardiac surgery. However, two critical barriers to the clinical management of these critically ill patients remain the need for better methods for early prognosis/diagnosis of AKI and therapeutic options to prevent/mitigate AKI. Uncontrolled inflammation is a leading cause of AKI. Injured cells in organs remote from the kidney (e.g. heart, brain, lungs, limbs) release UDP-glucose (UDP-G), a danger-associated molecular pattern (DAMP) molecule, which then builds up in the kidney, triggering inflammation. Consistent with this, we have data suggesting that high level of UDP-G in the urine of patients is predictive of the onset of AKI. We previously showed that UDP-G binds to the purinergic receptor P2Y14 in the kidney. This binding increases the expression of chemokines that attract neutrophils into the kidney. In studies supported by a B-BIC Pilot award, we demonstrated that prophylactic blocking of the UDP-G/P2Y14 signaling pathway with a potent, selective P2Y14 antagonist, PPTN, reduced renal inflammation and histological damage and improved renal function after renal ischemic reperfusion injury in mice. To complement this therapeutic approach, the aim of this DRIVE Award proposal is to develop a clinical-grade UDP-G assay for the prognosis/diagnosis of AKI. This can serve as a stand-alone diagnostic for AKI or as a theranostic for P2Y14-targeted therapeutics. 06/01/2019 Massachusetts General Hospital B-BIC image of external link icon Small molecule drug Acute Kidney Injury Associated with Cardiovascular Available
A Rapid, Inexpensive Platelet Function Test Robert Flaumenhaft Antiplatelet agents such as clopidogrel and aspirin are used in the treatment of heart attacks and strokes and are among the most commonly used drugs in the U.S. Problems associated with these drugs include bleeding risk (which complicates invasive procedures) and resistance (which can be overcome by alternative antiplatelet drugs). These common problems can be managed by platelet function monitoring. Current methods for monitoring platelet function, however, require expensive equipment, pricey consumables, and provide complicated readouts. These global approaches to platelet function are not widely used because their cost far exceeds reimbursement for the tests. We have developed a rapid, inexpensive platelet function immunoassay for use either in seamless conjunction with standard high throughput analyzers operating in clinical laboratories or as stand-alone devices. This immunoassay is based on our mapping of the unique signaling pathway leading to Drp1 phosphorylation. We find that phospho-Drp1 is exquisitely sensitive to all commercially available antiplatelet agents tested, including aspirin and clogpidogrel. The phospho-Drp1 signal is stable over time and can be used in conjunction with a total Drp1 value to provide a ratio that tolerates differences in blood draw volumes and platelet counts. The test is rapid and relies only on inexpensive reagents. This practical approach to testing platelet function in the context of antiplatelet therapy will fill an unmet clinical need in the doctor's office and in hospitals to help doctors manage their patients who receive these commonly used drugs for life-threatening indications. 04/01/2019 Beth Israel Deaconess Medical Center B-BIC image of external link icon Diagnostic device To measure platelet function in whole blood sample Option to license
PR1P, an inhaled novel short peptide for Acute Lung Injury and ARDS Benjamin Matthews ARDS is an acute inflammatory lung disease characterized by hypoxemia and multi-organ failure with a mortality reaching 50%. It accounts for almost 200,000 ICU admissions yearly in the US and thus impacts substantially on healthcare cost. Importantly, there are no drugs that treat ARDS. Disease progression is due in part to dysregulation of the Vascular Endothelial Growth Factor (VEGF). We recently designed a novel short peptide, PR1P, that binds and upregulates endogenous VEGF signaling. Preliminary work from our BBIC Pilot grant showed that inhaled PR1P mitigated acute lung injury (ALI) in an elastase-induced murine emphysema model. We hypothesize that PR1P will be therapeutic in humans with ARDS. The peptide requires proof-of-principle testing in animal and human models. We propose here in Aim 1 to characterize the effect of inhaled PR1P on disease progression in three established murine ARDS models, and in Aim 2 to determine if the therapeutic activity of the peptide is preserved in tissue samples from patients with ARDS. Mice will be treated with inhaled PR1P at different stages of disease to mimic treatment start times of patients presenting with ARDS. We will characterize the ability of PR1P to mitigate disease severity including 1) lung cell apoptosis, and lung 2) inflammation, 3) permeability and 4) damage. Our overall goal is to determine that PR1P mitigates murine ALI and is functional in human tissue samples. If successful, this will provide the proofs of concept necessary to support investment in PR1P for use in humans with ARDS. 02/01/2019 Boston Children's Hospital B-BIC image of external link icon Small molecule drug Acute Lung Injury and ARDS Available
CardioptOx: A new real-time quantitative Cardio-Pulmonary Monitoring Technique for Improved Patient Care Darren Roblyer Approximately 600,000 deaths per year are attributed to cardiopulmonary disease in the US. Many patients suffering from cardiopulmonary disease experience complications that require hospital and intensive care unit (ICU) stays. For these patients, constant monitoring of the adequacy of tissue oxygenation is essential. Despite the importance of tissue oxygenation, current techniques are limited by their inability to measure key parameters in both the arterial and venous vascular compartments, and by the invasive nature of their implementation (e.g. invasive catheters), leading to complications, false diagnoses, and high costs. Our invention is called CardioptOx, and is a new high-speed tissue oximetry technology that can be used by physicians to monitor oxygen supply and consumption in a better way. CardioptOx has the potential to be implemented in a wide variety of hospital settings representing broad patient impact and a substantial market size, including but not limited to continuous monitoring in the ICU. CardioptOx will address unmet needs, improve outcomes, and reduce costs in the ICU by providing physicians will better, non-invasive, and quantitative indications of tissue oxygenation and utilization that can be used to make decisions regarding interventions. This B-BIC pilot award will allow us to develop an improved human interface and analysis software for CardioptOx, and demonstrate equivalence to invasive methods. This will allow us to rapidly move towards the first in vivo clinical study of a targeted patient population, helping to move the technology towards FDA clearance and commercialization. 11/01/2018 Boston University B-BIC image of external link icon Diagnostic device cardiopulmonary disease Available
A Wearable Device for Diagnosis of Obstructive Sleep Apnea (OSA) Claus-Peter Richter The Obstructive Sleep Apnea (OSA) diagnostic device is a combination of sensors placed onto a neck collar to be worn at night. The sensors include arrays of small microphones, optical sources in the red, infrared, and electrical contacts. This wearable device uses recorded parameters and modern algorithms of machine learning to predict upcoming events such as snoring, hypopnea or apnea 08/01/2018 Northwestern University NCAI-CC image of external link icon Combination product Sleep Disorders Available
Transcatheter Mitral Repair with Basal Aneurysm Subvalvular Spacer (MBASS) Jose Navia Dr. Navia and Dr. Kapadia have developed a novel transcatheter subvalvular repair technique to place an implant in the basal aneurysm location for functional itral valve or tricuspid valve regurgitation patients. The role of the implant is to bring a mitral or tricuspid leaflet forward toward a medial position and close the ap with its neighboring leaflet structures: While one leaflet beats, the other is stationary in a favorable position. This displacement has been shown to be effective in resolving functional mitral valve regurgitation. The implant has been designed and the goal of this NCAI project is to further tackle product development on a delivery system and product integration with the vision to have an FDA discussion during the span of the project period. 08/01/2018 Cleveland Clinic NCAI-CC image of external link icon Therapeutic device functional itral valve or tricuspid valve regurgitation Available
Application of Combined Flow Pulsations and Acoustic Vibrations for Efficient Iris Gutmark-Little We have developed a bench-top prototype of a new airway clearance device for detaching and removing airway secretions by imposing coordinated airflow and acoustic pulses. The device can be tuned to patient-specific airway size and mucus physical properties. Our device was shown to be significantly more elective in mucus clearance when compared to commercially available devices. We seek funding to move the prototype closer to commercialization by making it more ergonomic and characterizing it for different disease states, with feedback from pulmonary professionals, patients, and potential licensees. 08/01/2018 Cincinnati Children's Hospital Medical Center NCAI-CC image of external link icon Therapeutic device mucus clearance Available
Pericelle: A Nanoparticle Based Perivascular Drug Delivery System to Prevent Stenosis and Failure in Vascular Reconstruction Surgeries Craig Kent Our product (Pericelle, all-inclusive kit) combines 1) a unimolecular micelle nanoparticle and 2) a &acirc;triblock&acirc; hydrogel, which together, facilitate local and sustained delivery of the anti-restenotic drug, rapamycin (Figure 1 and ref 6). Given the high rates of stenosis and graft failure in open vascular reconstruction surgeries, a preventative therapeutic strategy is warranted, as has been accepted for endovascular rapamycin eluting stents. 08/01/2018 Ohio State University NCAI-CC image of external link icon Combination product AV Fistula and Vein Bypass Graft open Surgeries Available
Repurposing Barasertib for the Treatment of Pulmonary Fibrosis Anil Jegga Idiopathic Pulmonary Fibrosis (IPF) is a chronic fibrotic lung disease that involves the progressive accumulation of mesenchymal cells due to their excessive proliferation and survival. Nintedanib and pirfenidone are two recently FDA-approved therapies that slow the rate of decline in lung function in patients with IPF, but do not halt progression or reverse fibrosis; thus, newer therapies that inhibit fibroblast activation to reverse established and ongoing fibrosis would have significant advantages over these current agents. Although multiple pro-fibrotic growth factors intensively studied, the molecular pathways that synergistically regulate fibroblast phenotypes have not been identified and constitute a fundamental knowledge gap in the field. Our preliminary findings demonstrate that Aurora Kinase B (AURKB) represents a targetable downstream point where multiple upstream fibrogenic pathways converge to cause excessive proliferation and survival in fibroblasts. The objective of the proposed study is to develop an effective formulation and aerosolized delivery methods to determine the efficacy of a highly selective AURKB inhibitor, Barasertib (AZD1152) that can prevent the progression and reverse fibrosis in mouse models of pulmonary fibrosis. Barasertib is well tolerated in multiple cancers with favorable safety data and showed anti-tumor activity. Importantly, our new findings suggest that barasertib administered intraperitoneally (IP) attenuates fibroblast activation and pulmonary fibrosis in vivo. Since IPF requires prolonged treatment, IP administration is undesirable and impractical for patients. Hence, a targeted therapeutic pressurized aerosol delivery method that (i) can be given at smaller doses compared to systemic treatment; (ii) has rapid onset of drug action; and (iii) has lesser systemic side effects is proposed. The proposed studies focusing on nebulization of barasertib are therefore important and critical in moving this lead compound to become a clinical candidate for IPF. The major goals of this application are (i) to develop an optimal aerosol formulation of barasertib, and to establish preclinical therapeutic dose for barasertib dry powder formulation in pulmonary fibrosis. The culmination of this work will enable future innovative Phase I/II IPF clinical trials using barasertib. 08/01/2018 Cincinnati Children's Hospital Medical Center NCAI-CC image of external link icon Small molecule drug Idiopathic Pulmonary Fibrosis Available
Ultrawideband Radio-Frequency Imaging Technology for Monitoring Thoracic Fluid Levels, Heart and Lung Motion to Predict Heart Failure Events Emre Ertin EasySense is a non-invasive technology developed at the Ohio State University that measures thoracic fluid levels, cardiac and lung motion by transmitting ultrawideband radio frequency pulses and analyzing the backscattered waves. Non-invasive measurements with the EasySense system provide biomarkers to assess status of heart failure patients. EasySense monitoring system can be used both at home setting as well as in the clinic to assess the lung water volume and distribution enabling the physician to adjust the treatment regimen with an aim to minimize the risk of rehospitalization. 08/01/2018 Ohio State University NCAI-CC image of external link icon Combination product Heart failure Available
Critical Health Assessment &amp; Outcomes Study/Score (CHAOS) for Improved Personalized Prediction of Impending Adverse Events Before Clinical Presentation Deeptankar DeMazumder CHAOS is comprised of novel artificial intelligence algorithms, methods, computer product, apparatus and HIPAA-compliant data retrieval, storage, analytical and display system for enhanced and highly personalized dynamic predictive monitoring (DPM). Many illnesses progress asymptomatically and by the time these illnesses present clinically, irreversible organ system damage has often begun. A working &acirc;bed-to-DPM&acirc; and &acirc;DPM-back-tobed&acirc; CHAOS infrastructure, the intended overall goal of this proposal, will identify &acirc;hidden&acirc; subclinical critical illness in individuals before clinical presentation [e.g., sudden cardiac death, heart failure decompensation, shock]. This will provide more lead time for healthcare providers to prepare, assess reversible or preventive causes, and to deliver more planned, appropriate, efficient, effective and best practice-driven therapies. This would then be expected to reduce length of hospital stay and costs by avoiding complications associated with delayed treatment. Further, CHAOS-based risk stratification will lead to safer hospital discharges, fewer repeat hospitalizations, and more appropriate selection of recipients for advanced life-saving therapies that otherwise are costly, limited in availability and have high risk of procedural complications. This proposal aims to establish the necessary infrastructure at the University of Cincinnati to complete demonstration of feasibility, safety and efficacy for CHAOS and enable progression to the next steps for commercial translation. 08/01/2018 University of Cincinnati NCAI-CC image of external link icon Health information technology various Available
Therapeutic Product to Treat Arrhythmia Ohyun Kwon "Through a chemical suppressor screen on a zebrafish cardiac arrhythmia model, we have identified a small molecule, named &acirc;efsevin&acirc;, as a chemical defibrillator and its target protein, VDAC2, as a novel modulator of cardiac Ca2+ handling and a therapeutic target for the treatment of cardiac arrhythmias. Our finding that efsevin potentiates VDAC2 activity and, thereby, allows cardiomyocytes to tolerate a higher frequency of Ca2+ sparks under Ca2+ overload conditions indicates that efsevin serves as a pharmacological tool that prevents the propagation of arrhythmogenic Ca2+ waves and provides a new class of therapeutic agents for cardiac arrhythmias in humans. Our project already has a validated target (VDAC) in zebrafish, as well as in mouse and human cardiomyocytes. In addition to the in vivo fish model, we have tested efsevin in an in vivo murine model for human cardiac arrhythmia [catecholaminergic polymorphic ventricular tachycardia (CPVT)]. We have also examined efsevin in a ventricular fibrillation (VF) model in aged rat hearts. Clearly, efsevin has demonstrated clinical indications in cardiac arrhythmias and fibrillation, suggesting great potential for significant improvements over current treatments. In this grant application, we propose a two-pronged approach for executing the preclinical phase of the project: 1] a medicinal chemistry campaign to refine the PK/PD/Tox properties of our lead; 2] an evaluation of our lead in clinically relevant animal models of arrhythmia. " 08/01/2018 UCLA UC-CAI image of external link icon Small molecule drug Heart Failure, CPVT, Atrial Fibrillation Technology licensed to startup
Small molecules to inhibit ectopic calcification of soft tissues Arjun Deb Ectopic calcification refers to pathological mineralization of extra skeletal soft tissues and commonly occurs with age, common diseases such as diabetes and chronic kidney disease and orphan genetic disorders such as Pseudoxanthoma Elasticum (PXE). The heart, heart valves and vasculature are particularly susceptible to and are the commonest tissues undergoing ectopic calcification. Calcification of the heart, heart valves or blood vessels leads to disruption of structural homogeneity and leads to organ dysfunction. For instance, calcification of the blood vessels regardless of etiology causes luminal narrowing, hypertension, prevents auto-regulation of vasomotor tone and leads to a substantial increase in cardiovascular mortality from target organ ischemia or hemorrhage. The mortality of children/young adults with end stage chronic kidney disease increases 100 fold secondary to calcific vascular disease. Ectopic calcification of the aortic valve leads to aortic stenosis and requires surgical replacement of the aortic valve. Genetic syndromes such as Pseudoxanthoma Elasticum (PXE) also cause ectopic calcification of the heart and vasculature and lead to premature heart disease and ischemic syndromes from calcific narrowing of blood vessels. Despite the immense pathologic importance of ectopic calcification of the heart and vasculature, little is understood about the biology of ectopic calcification. The molecular details of the process remain incompletely defined and currently there is not a single drug that retards calcification. We have recently identified a novel target, Ectonucleotide Pyrophosphatase-1 (ENPP1) for the treatment of ectopic calcification. We show that ENPP1 is dramatically upregulated in calcifying tissues both in mouse models of PXE and in human tissues undergoing ectopic calcification. ENPP1 is a cell surface protein and acts like an enzyme to hydrolyze ATP into AMP and pyrophosphate (PPi). Pyrophosphate then serves as a substrate for inorganic phosphate (Pi) generation by hydrolytic activity of tissue non specific phosphatases. Thus excess ENPP1 activity generates PPi and consequently a large amount of Pi that complexes with extracellular calcium to form calcium hydroxyapatite deposits. We have performed small molecule screening of more than 200,000 compounds and identified small molecule ENPP1 inhibitors and confirmed our primary hits with secondary assays with orthogonal readouts. Using such molecules in vivo, we demonstrate that ENPP1 inhibition leads to attenuated calcification in vivo in a mouse model of PXE as well as in a human pluripotent stem cell model of PXE in vitro. Considering these observations and taking into account prior suggestions by reviewers to focus on an orphan disease as the most rapid strategy of developing a therapy for ectopic calcification, we have focused this application on identifying a lead small molecule candidate for preventing calcification in the orphan disease PXE. PXE is characterized by dramatic up-regulation of ENPP1 in calcifying tissues and thus represents an ideal platform for establishing a therapeutic strategy for the treatment of ectopic calcification. We thus propose to develop a lead small molecule candidate inhibitor of ENPP1 that would attenuate ectopic calcification in a human pluripotent stem cell model of PXE as well as in vivo in a mouse model of PXE. Such proof of concept would then be extended in the future into using our lead candidate to prevent ectopic calcification in other common causes of ectopic calcification such as calcific aortic valve disease or vascular calcification in chronic kidney disease. This strategy suggested by multiple reviewers and adopted in this proposal thus enables the rapid interrogation of calcification in PXE with existing resources in the lab and potentially establishes a lead small molecule for ectopic calcification which then can be applied for other causes of ectopic calcification such as in CKD or valve disease. 08/01/2018 UCLA UC-CAI image of external link icon Small molecule drug Ectopic calcification in Pseudoxanthoma Elasticum Available
Hemodynamic Monitoring for Peripheral Vascular Diseases using Wearable Ultrasonic Bandages Sheng Xu This proposed project aims to develop a soft wearable transducer array for continuous, accurate, and non-invasive measurement of blood flow velocity waveforms in patients with peripheral vascular diseases (PVD). The blood flow velocity waveform can provide critical information about the major organ activities and psychiatric state changes, which would help raise patient awareness, assist preventive care, and serve as the basis for personalized medicine. Conventional measurement protocols include catheter implants, which is invasive and risky, and Doppler ultrasonography, which is heavily user-dependent and often has errors and artifacts. This research is distinct from the existing methods, because it offers several unique features. First, due to its low-profile form factors, the wearable ultrasonic device enables continuous measurement of the blood flow velocity waveform without constricting the natural movement of the subject. Second, this device has similar mechanical properties to the human skin and therefore can achieve conformal and intimate contact with the skin, which allows accurate and stable measurements. Third, the phased array control mechanism facilitates focusing and steering the ultrasonic beam at any locations with predefined incident angles, which enhances the signal-to-noise-ratio and removes user errors for manual operations. Towards that end, by combining materials science, mechanical design, and electronics integration, we will optimize the performance of a single ultrasonic transducer. Then, we will develop phased array control mechanism on a wearable platform to achieve ultrasonic beam focusing and steering. After that, we will clinically validate the stretchable transducer array with the phased array control circuit to achieve continuous and accurate recording of blood flow velocity waveforms. The proposed research is the first of its kind to use a soft, stretchable system to diagnose and monitor deep tissues under the skin. Successful completion of this project will have a direct impact on clinical practice, revolutionizing the monitoring of patients with PVD and creating significant savings in both time and money by limiting the need for highly-trained personnel while at the same time greatly improving patient safety and most importantly, outcomes. 08/01/2018 UCSD UC-CAI image of external link icon Diagnostic device Peripheral Vascular disease (PVD) Available
Small Molecule Inhibitors of Integrin alpha2beta1 to mitigate smooth muscle contraction in asthma Dean Sheppard Severe asthma accounts for approximately 10% of the 300 million people worldwide that carry a diagnosis of asthma. These patients have persistent symptoms of exaggerated airway narrowing despite standard treatments including anti-inflammatories (corticosteroids) and muscle-targeted therapies (&Atilde;&Acirc;&sup2;-adrenergic agonists). Though biologics that target specific cytokine pathways have emerged as a new approach to treatment of severe asthma, they are only injectable and early clinical trials have shown inconsistent benefit only in a small subset of severe asthmatics. Thus, development of new asthma therapeutics with a novel mechanism of action is urgently needed. In the preliminary data of this proposal, we show that integrin alpha2 beta1 plays an important role in mediating adhesion of airway smooth muscle to collagen, an extracellular matrix protein highly upregulated in the asthmatic airway. We show that pharmacological blockade of this integrin by c15 reduces cytokine-enhanced force transmission ex vivo, protects against airway hyperresponsiveness in vivo, and enhances the effect of currently available bronchodilators. However, use of c15 as a lead compound is limited by poor cell permeability and short in vivo half-life. From initial studies to improve pharmacokinetic properties, we identified an alternative chemical scaffold with comparable potency to c15. The purpose of the current proposal is to develop an alpha2beta1 inhibitor in novel IP space that is optimized for inhaled delivery. Such a drug could be used either alone or in conjunction with other currently available therapies to enhance smooth muscle relaxation in patients suffering from severe persistent asthma. Such an approach has the potential to benefit the patients with severe asthma and would be an important addition to the otherwise limited options for smooth-muscle targeted therapy in acute exacerbations of asthma. 08/01/2018 UCSF UC-CAI image of external link icon Small molecule drug Asthma Available
Peptide inhibitors of Porphyromonas gingivalis fimbrial assembly for the prevention of periodontal disease Sarah Alaei Abstract: The goal of this research is to develop inhibitors of Porphyromonas gingivalis infection. P. gingivalis is a key bacterial pathogen involved in the chronic inflammatory disease, periodontitis, which is caused by dysbiosis of the oral microbiota. This disease impacts the lives of millions of people worldwide by causing damage to teeth and their supporting tissues, and increasing the risk of developing heart disease, diabetes, rheumatoid arthritis and other serious conditions. Hair-like surface structures termed fimbriae are used by P. gingivalis to adhere to host cells and other bacteria, enabling colonization of the oral cavity. Based on our preliminary studies, we hypothesize that peptides corresponding to the C terminus of the Mfa1 fimbrial subunit protein can be used to inhibit fimbrial assembly and thereby reduce the adhesive capabilities of P. gingivalis. We will first test peptide sequences derived directly from the C terminus of Mfa1 for their ability to inhibit fimbrial assembly. Subsequently, we will utilize computational methods to optimize the peptide sequences, improving their affinity for Mfa1 and other biophysical properties. This work will be carried out by an interdisciplinary team of investigators with expertise in the analysis of fimbrial biogenesis, bacterial pathogenesis, and computational modeling of protein-protein interactions. 07/01/2018 Stony Brook University LIBH image of external link icon Biologic drug Periodontal disease Available
Closed-Loop Titration of Vasopressor Infusions for ICU and OR Care Joseph Rinehart The world is on the cusp of having self-driving cars &acirc;a science-fiction dream since the invention of the automobile&acirc; yet virtually all of our medical monitoring systems have no function beyond displaying data to clinicians who then must take action based on that data. If computer systems can drive cars safely (indeed they have flown commercial airlines safely for decades), surely there is more they can be doing for patient care than just displaying numbers on a screen? The last five years of my research career were spent developing a closed-loop system for intraoperative fluid management, a long project which culminated in sublicensing of the IP at the end of 2014 to Edwards Lifesciences for commercialization and which will be (if current timelines remain good) hitting the European market in Spring of 2017 and the American market later next year. Our attention now turns to patients in the intensive care or operating room who physicians determine are in need of vasopressor infusions to maintain blood pressure. If the infusion is set too low hypotension results and organ ischemia may follow, leading to kidney injury, strokes, cardiac ischemia, and organ failure. Too much vasopressor may cause digit ischemia with subsequent dry gangrene, or in extreme cases bowel ischemia with severe morbidity and mortality. Thus, having "just enough" vasopressor to meet physiologic needs is critical. Vasopressor infusions must presently be titrated by hand by bedside providers to meet blood pressure objectives. This arrangement leads to inconsistency in timing and management across different providers, many of whom are already heavily tasked with other responsibilities, sometimes across more than one patient. Moreover, from a healthcare-systems view, the underlying variability between (and even within) each patient's hour-to-hour drip management represents a variable that is presently extremely difficult to control. Titration is a task a computer controller could perform well and represents an opportunity to have a major fundamental impact on how vasodilatory hypotension is managed. Initial development of a such novel closed-loop controller for control of vasopressor has been completed, with engineering work and an animal study now completed and strongly supporting the efficacy of our system. With our provisional patents now filed as well, we are prepared to launch our full commercialization effort. The NHLBI Technology Development award represents a unique opportunity for us to gather the remaining information investors will seek when we form a company and go to secure outside funding. 08/01/2018 UC Irvine UC-CAI image of external link icon Therapeutic device Blood pressure maintenance Available
Closed-Loop Titration of Vasopressor Infusions for ICU and OR Care Joseph Rinehart The world is on the cusp of having self-driving cars &acirc;a science-fiction dream since the invention of the automobile&acirc; yet virtually all of our medical monitoring systems have no function beyond displaying data to clinicians who then must take action based on that data. If computer systems can drive cars safely (indeed they have flown commercial airlines safely for decades), surely there is more they can be doing for patient care than just displaying numbers on a screen? The last five years of my research career were spent developing a closed-loop system for intraoperative fluid management, a long project which culminated in sublicensing of the IP at the end of 2014 to Edwards Lifesciences for commercialization and which will be (if current timelines remain good) hitting the European market in Spring of 2017 and the American market later next year. Our attention now turns to patients in the intensive care or operating room who physicians determine are in need of vasopressor infusions to maintain blood pressure. If the infusion is set too low hypotension results and organ ischemia may follow, leading to kidney injury, strokes, cardiac ischemia, and organ failure. Too much vasopressor may cause digit ischemia with subsequent dry gangrene, or in extreme cases bowel ischemia with severe morbidity and mortality. Thus, having "just enough" vasopressor to meet physiologic needs is critical. Vasopressor infusions must presently be titrated by hand by bedside providers to meet blood pressure objectives. This arrangement leads to inconsistency in timing and management across different providers, many of whom are already heavily tasked with other responsibilities, sometimes across more than one patient. Moreover, from a healthcare-systems view, the underlying variability between (and even within) each patient's hour-to-hour drip management represents a variable that is presently extremely difficult to control. Titration is a task a computer controller could perform well and represents an opportunity to have a major fundamental impact on how vasodilatory hypotension is managed. Initial development of a such novel closed-loop controller for control of vasopressor has been completed, with engineering work and an animal study now completed and strongly supporting the efficacy of our system. With our provisional patents now filed as well, we are prepared to launch our full commercialization effort. The NHLBI Technology Development award represents a unique opportunity for us to gather the remaining information investors will seek when we form a company and go to secure outside funding. 08/01/2018 UC Irvine UC-CAI image of external link icon Therapeutic device Blood pressure maintenance Available
Development Biomimetic luminal coating capture endothelial progenitor cells, improve outcomes following balloon angioplasty Alyssa Panitch Drug-eluting stents (DESs) have been used widely due to their ability to prevent restenosis. However, a complication of DESs is development of late in-stent thrombosis at the same rate as the bare metal stents (BMSs). The DESs used in clinical application to deliver an anti-proliferative agent, such as sirolimus or paclitaxel (PTX), which inhibits not only smooth muscle cells (SMCs) proliferation, but also prevents proliferation of endothelial cells (ECs). While drug-eluting stents were developed to combat neointimal hyperplasia, reports in the New England Journal of Medicine by Bonna, et al. demonstrate that the 6-year primary outcomes for drug-eluting stents are no better than those of bare metal stents suggesting that new approaches are critical. The main objective of this project is utilize our in vitro and in vivo models in order to test novel therapies that will control thrombosis and inflammation and promote re-endothelialization of the damaged vessel, and therefore, intimal hyperplasia, thus improving the outcomes for PCI. The hypothesize of this proposal is that deliberate capture of circulating endothelial progenitor cells (EPC) by addition of addition an EPC ligand to the previously developed antiplatelet arterial paving molecule DS-SILY, will result in a molecule that can be delivered from the end of a catheter following balloon angioplasty to coat the collagen exposed areas, prevent platelet binding and thrombosis, support capture of EPCs from blood to facilitate reendothelialization, and reduce late-lumen loss (neointimal hyperplasia). To address this hypothesis we have developed two specific aims in which we will optimize collagen-binding to enhance binding to the injured arterial wall and increase in vivo residence time; incorporate peptides to capture EPCs to rapidly re-endothelialize the damaged blood vessel while maintaining the ability to suppress platelet binding and thrombosis. Finally, we will assess the therapeutic in an in vivo porcine atherosclerosis model of PCI. At the end of the proposed studies we will have a simple, easily delivered, vessel coating that is targeted to inhibit thrombosis and SMC proliferation, and promote reendothelialization, which will be ready for translation to improve the outcomes of PCI procedures. Importantly, the technology is designed to work with current clinical practice and will not affect operating room procedures or time. 08/01/2018 UC Davis UC-CAI image of external link icon Small molecule drug Reduce platelet binding to luminal surface of blood vessel grafts Available
High-Throughput Site-Specific Gene Modification of the Sickle Cell Disease Mutation via Microfluidic Mechanical Deformation Paul S. Weiss The development of autologous gene-modified hematopoietic stem cell transplantation (HSCT) strategies would revolutionize the management of sickle cell disease (SCD) by expanding patient access to definitive therapy in place of traditional supportive treatments. These approaches have traditionally relied on viral-based transfection methods that are costly and prone to potential off-target effects (e.g., insertional mutagenesis). More recently, genome-editing methods based on targeted nuclease technologies (e.g., clustered regularly interspaced short palindromic repeat nucleases, CRISPR) have been developed to enable coordinated gene disruption or insertion of new DNA sequences at preselected sites. However, these constructs are delivered to cells via non-viral transfection methods (e.g., electroporation) that are limited by toxicities and inefficient gene transfer at clinically relevant scales. There is a critical unmet need for methods capable of processing cells quickly, with high efficiency and recovery rates to enable the generation and recovery of more homogeneous, safe, and better characterized stem-cell products for emerging gene and cellular therapies. Leveraging previous successful prototyping and proof-of-concept testing enabled by our UC CAI Stimulus Award, we focus on developing and applying a new high-throughput, safe, economical gene-delivery and HSPC processing technology where target cells are rendered porous transiently via mechanical manipulation of their cellular membranes by acoustic waves to enable correction of the SCD mutation via CRISPR-based-gene-editing. Our technology is scalable and compatible with good manufacturing practices, circumventing major obstacles to the translation and clinical deployment of effective gene-therapies for SCD. We have been engaged with the UCLA Technology Development Group to secure patent rights to this technology explore the formation of industrial partnerships to support accelerated development toward commercialization of viable gene therapies. 08/01/2018 UCLA UC-CAI image of external link icon Combination product Severe sickle-cell disease Available
Antibody&acirc;mediated inhibition of PTP-Sigma for hematopoietic regeneration Heather Himburg Abstract PI: Heather Himburg Co-PI: Peter Bowers Proposal Title: Antibody&Acirc;mediated inhibition of PTP-Sigma for hematopoietic regeneration Systemic therapies that can promote the self-renewal or regeneration of hematopoietic stem cells (HSC) in vivo could have broad therapeutic benefits for patients receiving myelosuppressive chemotherapy or radiotherapy, those undergoing hematopoietic cell transplantation, and for patients with aplastic anemia. However, the development of such HSC regenerative therapies has been thwarted by the lack of understanding of the mechanisms that regulate HSC regeneration. We have discovered a unique transmembrane protein tyrosine phosphatase (PTP), PTP-sigma, which is expressed by murine and human HSCs and which strongly regulates HSC regeneration in vivo. Mice bearing genetic deletion of PTP-sigma (PTP-sigma-/- mice) displayed 10-fold increased HSC repopulating capacity when transplanted competitively into congenic mice, compared to PTP-sigma +/+ mice. Furthermore, the negative selection of human cord blood HSCs for PTP-sigma expression yielded a 15-fold enrichment for human PTP-sigma-negative HSCs compared to human cord blood PTP-sigma+ cells. Interestingly, PTP-sigma-/- HSCs expressed significantly increased levels of activated Rael, a RhoGTPase that promotes HSC self-renewal. Inhibition of Rael significantly abrogated HSC colony formation and transendothelial migration capacity of PTP-sigma -deficient HSCs. We have subsequently developed several PTP-sigma inhibitors with novel composition of matter and have demonstrated that systemic administration of such PTP inhibitors promote hematopoietic regeneration in vitro and in vivo. To develop specific and potent PTP-Sigma inhibitors we propose herein to generate agonistic monoclonal antibodies against human PTP-sigma that are capable of accelerating human hematopoietic regeneration in patients receiving myelosuppressive chemotherapy or radiotherapy and patients undergoing hematopoietic cell transplantation. 02/01/2018 UCLA UC-CAI image of external link icon Biologic drug Anemia Available
Living Synthetic Vascular Grafts with Renewable Endothelium Aijun Wang A functioning vascular access is necessary for hemodialysis. Arteriovenous polytetrafluoroethylene (PTFE) dialysis grafts remain the most common form of hemodialysis vascular access in the U.S. because they are relatively easy to apply and available off-the-shelf. However, they have extremely high failure rates due to thrombosis, stenosis, and infection. It was reported that the primary graft survival (time from graft placement to the first intervention) was only 23% at 1 year and 4% at 2 years. Thus, there is a critical clinical need for vascular grafts that can maintain superior patency. PTFE grafts possess no regenerative or growth potential and the major cause of their high failure rate is the lack of functional endothelium. There is great need to develop technology that enables generation of self-renewable &Acirc;living&Acirc; endothelium on the luminal surface of synthetic vascular grafts. Various biomacromolecules have been applied to coat the vascular grafts to recruit circulating endothelial cells (EC) and/or endothelial progenitor cells (EPCs) from the blood stream to facilitate endothelialization. However, most of these large proteins are not structurally stable, making chemical manipulation and product shipping/storage technically challenging. A molecule that has high binding affinity and specificity to ECs and EPCs is needed. One-Bead One-Compound (OBOC) combinatorial library technology is an ultra-high throughput screening method based on synthetic chemistry. Recently, using primary artery-derived ECs and blood-derived EPCs as living probes to screen OBOC peptide libraries, we have identified LXW7, a high-affinity binding ligand against the avb3 integrin, on the surface of EPCs/ECs. LXW7 binds strongly to primary EPCs/ECs, but weakly to platelets and does not bind to THP-1 monocytes. Furthermore, because (i) 4 out of 8 amino acids are D-amino acids, and (ii) it is cyclic, LXW7 is highly proteolytically stable, a critical requirement for in vivo application. To test the ability of LXW7 to promote endothelialization of synthetic grafts, we evaluated polymer-based small diameter vascular grafts functionalized with LXW7 via Click chemistry in a rat carotid artery bypass model. We found that LXW7-modified grafts showed significantly higher patency rate than the control grafts. After 6 weeks post-implantation, mature ECs were present throughout the whole length of the LXW7-modified grafts while only a limited number of ECs were identified in the middle segment of the control grafts, confirming that LXW7 coating generates a &Acirc;living&Acirc; endothelium on the luminal surface of synthetic vascular grafts. In this study, we propose to establish LXW7 as a potent ligand to modify the surface of vascular grafts to achieve improved in situ endothelialization. The routinely used PTFE vascular graft is used as a model for the study. We propose to adapt the chemical vapor deposition (CVD) polymerization protocol to introduce alkyne functional groups to the graft surface via alkyne-functionalized parylene, and then covalently ligate LXW7-linker-azide via Click chemistry. Parylene is chosen as the coating material because it possesses excellent mechanical properties in terms of flexibility and long-lasting in vivo adherence to the implant surface and the FDA has already approved Parylenes as Class VI polymers for coating medical devices due to their biocompatibility. We will perform in vitro experiments to confirm the functions including stability, cell type specificity, thrombogenicity and hemocompatibility of the LXW7-modified grafts. We will further test our prototype in an established pig arteriovenous graft model to determine device patency, thrombosis and neointimal hyperplasia and extent of endothelial ingrowth. Successful completion of this project will provide valuable basis for the development of LXW7-based surface modification for improved endothelialization to a wide range of intravascular devices, including cardiac valves and catheters. 12/01/2017 UC Davis UC-CAI image of external link icon Therapeutic device hemodialysis Available
Vectorcardiographic Mapping of the Sources of Ventricular Fibrillation David Krummen Ventricular fibrillation (VF) is a life threatening arrhythmia and a leading cause of the 700,000 annual cases of sudden death in the United States and Europe. Currently, there are no targeted treatments for VF that address its underlying mechanisms. Recent work from our lab found that VF rotor sites are spatially conserved across VF episodes. In a prospective VF rotor ablation, we demonstrated that that VF rotor ablation decreases VF inducibility and clinical events in patients with VF. This potentially represents a novel treatment paradigm in patients with clinical VF, and parallels our work showing improved ablation outcomes in atrial fibrillation. It would be clinically and financially beneficial to detect and localize VF rotors using noninvasive methods in order to identify candidates for targeted treatment and help guide the ablation of rotors, prior to invasive mapping. Our IP-protected invention can identify the source(s) of VF for each VF cycle. Analysis of an episode of induced VF (~10 seconds, 50 VF cycles) can provide a comprehensive understanding of VF source locations, which may guide invasive therapies such as ablation. 09/15/2017 UCSD UC-CAI image of external link icon Diagnostic device Ventricular fibrillation Technology licensed to startup
ASPIRE: Asthma Sensing Predictive Intuitive Respiratory E-alert Monitor Michelle Khine There is an unmet need for a device to automatically detect the onset of an asthma attack. Current monitoring technologies are manual, subjective and not continuous. Moreover, while inhaled corticosteroids are the preferred long-term treatment for asthma, these drugs have known significant adverse effects, especially in children. Surprisingly, there is currently no way to monitor the effectiveness of medication with the goal to adjust for the minimal dosage required. The ability to reduce the number and severity of incidences of asthma attacks that would require an inhaler, doctor, or hospital visit would result in significant cost savings to insurers and patients. We have developed a proprietary sensor plus app and crowd sourced mapping solution to detect, monitor, and prevent asthma attacks. Because asthma is the most common chronic disease of children and 75% of asthmatic attacks occur at night, an automated and continuous monitor that would detect an attack at its earliest onset, before it gets progressively worse, would save lives and significant health care costs. 02/01/2018 UC Irvine UC-CAI image of external link icon Health information technology Asthma Option to license
A Diagnostic Tool to Identify Patients at Increased Risk of Forming Thrombi in the Cardiac Left Ventricle Juan del Alamo Intraventricular thrombus formation in patients with left ventricular (LV) systolic dysfunction is an important clinical problem that contributes to the incidence of systemic thromboembolism and stroke. Patients with LV systolic dysfunction and normal sinus rhythm have an incidence of stroke five times higher than controls, and thousands of them suffer stroke in the United States every year. However, the vast majority of these patients are not treated with anticoagulants because this treatment increases the risk of major bleeding and it has not proven effective in unselected patients with LV systolic dysfunction. Thus, there is a major clinical need for a diagnostic tool to identify patients at increased risk of developing LV thrombi who would benefit from anticoagulation. We have recently developed technology that, for the first time, offers an accurate patient-specific assessment of LV blood flow patterns and stasis by novel analyses of echocardiographic images, and hence can predict the risk of intraventricular thrombus formation. The basis for the technology is that LV blood stasis is known to increase the risk of thrombosis by initiating the coagulation cascade. Thus, understanding the role of blood flow in the genesis and evolution of intraventricular thrombi can improve the identification and clinical management of patients at increased risk of developing LV thrombi. Our software analyzes echocardiographic images obtained using standard equipment, does not require special operator training, and does not involve time-consuming post-processing. Thus, it can be immediately transferred to the clinical setting to guide personalized decisions regarding the use of anticoagulant therapies. We and collaborators have tested a beta version of this software and shown that it is predictive of thrombi formation in patients with recent anterior myocardial infarctions. In the current proposal, we plan to develop this technology into a commercial software product that can be deployed clinically. To accomplish this goal, we will expand the research-grade prototype version of our software into the minimum viable product stage, compatible with the major echocardiographic vendors, and with a user-friendly graphical interface. In addition, we will perform testing to demonstrate the reproducibility of the data and to test the sensitivity of the product to input data variability (both inherent to the patient and operator dependent) and signal noise. The outcome of the project would achieve several major inflection points in the value of our technology. The viable product can be sold to early adopters and will be used in the clinical trials required to obtain FDA approval. Additionally, showing that our product is being used in hospitals will showcase our technology to investors and purchasers. Furthermore, we will gather valuable feedback to improve the functionalities of our software. This outcome will open several viable exits, including partnership with large manufacturers of medical imaging hardware or pharmaceutical manufacturers of novel oral anticoagulants. Additional potential exits are competing for NIH SBIR/STTR/Clinical Trial funding and obtaining venture capital financing. The planned product is applicable to a large and growing patient population, and could enable a paradigm shift towards personalized, evidence-based management of a large group of patients at risk of cardioembolic stroke. In the U.S. alone, over 700,000 people suffer myocardial infarctions per year, and there are over 500,000 new diagnosed cases of heart failure due to LV dysfunction every year. Thus, the commercialization of our technology will potentially lead to improved treatment of hundreds of thousands of patients, resulting in decreased morbidity, mortality, and healthcare costs. Additionally, we estimate that the high cost of stroke management ($44,000/patient/year) will drive the willingness to pay for health insurance providers. 09/15/2017 UCSD UC-CAI image of external link icon Diagnostic device N/A Available
Efficacy of Yohimbine as a Drug Treatment for Obstructive Sleep Apnea Luigi Taranto-Montemurro Obstructive sleep apnea (OSA), a chronic breathing disorder during sleep, is a major public health concern because of its prevalence and many potentially life-threatening sequelae. Current standard treatment using continuous positive airway pressure (CPAP) to restore upper airway patency is effective but has a poor adherence rate, whereas alternative treatments are generally less effective and not suitable for all patients. Effective pharmacotherapy is currently an unmet need for the management of patients with OSA. In this application, we propose a novel drug treatment of OSA using a new (time-release) formulation of yohimbine, a prescription drug which historically has been used for off-label treatment of erectile dysfunction (ED). In previous preclinical studies, our consultant Dr. Poon found that yohimbine (an &Icirc;&plusmn;2-adrenergic blocker) was highly effective in reversing the noradrenergic-dependent decrease in hypoglossal activity during sleep (particularly rapid-eye-movement sleep), which is the primary cause of the hypotonia of upper airway muscles in OSA. The purpose of this B-BIC project is to perform a first-in-man clinical evaluation of the efficacy of yohimbine therapy in adult OSA patients during sleep. The results will provide a proof-of-concept for the efficacy of yohimbine therapy in OSA patients as well as inform future development of a safe-to-use, time-release formulation of yohimbine. These benchmark data will help attract investment interest from pharma and VC companies for further product development. 06/01/2018 Brigham and Women's Hospital B-BIC image of external link icon Small molecule drug Sleep Apnea Available
Wearable lactation device Joseph Hale For lactating mothers, current breast pumps are loud, bulky, and do not lend themselves to portability. Due to this, many women abandon breast feeding before the infant turns 6 months old. The proposed product would be a wearable breast pump that is discreet and has minimal parts in order to make pumping easier for the mother. 09/01/2017 University of Minnesota MN-REACH image of external link icon Therapeutic device Lactation Available
Tool for Endobronchial Biopsies of Peripheral Lung Nodules Michael Geminger Lung cancer bioposies in the periphery of the lungs are difficult with standard bronchoscopes are which are too large to access the smaller peripheral lung spaces. The proposed device incorporates ultrasound, video feedback and steerability in an instrument small enough to reach nodules in the lung periphery. 09/01/2017 University of Minnesota MN-REACH image of external link icon Therapeutic device Lung cancer Available
Topical application for treating a field of multiple actinic keratotic lesions Ann Bode The proposed topical cream is used for the treatment of actinic keratotic lesions, a non-melanoma cutaneous squamous cell carcinoma precursor. The proposed product is designed to eliminate the adverse side effects currently associated with standard actinic keratosis treatment, and in doing so, decrease the markedly high rate of patient non-compliance. 09/01/2017 University of Minnesota MN-REACH image of external link icon Small molecule drug Actinic keratotic lesion Available
Customer Interest in a Skin Damage Severity Assessment Instrument for Practice Donna Bliss Incontinence Associated Skin Damage due to fecal or urinary incontinence affects 20% to 35% of hospital patients, 50% of critically ill patients and 3% to 8% of long term care patients. The proposed product is an electronic version of the existing IASD assessment tool. The intent is to establish a standardized assessment scoring system across multiple cases and nursing personnel. 01/01/2018 University of Minnesota MN-REACH image of external link icon Health information technology Incontinence Associated Skin Damage Technology licensed to startup
LDL as biomarker for childhood tuberculosis (TB) Xinxin Yang Childhood tuberculosis (TB) is estimated to contribute 10-15% of the disease burden in high-burden settings and 74,000 children die from TB each year. Existing diagnostic tools fail to confirm TB in the majority of children, who typically have paucibacillary disease. In addition, the lack of diagnostics to distinguish between active TB and latent TB infection is a big obstacle in TB prevention. More sensitive and child-friendly diagnostic tools are urgently needed to diagnose both active and latent TB in children. Our proposed product is a rapid and non-sputum-based ELISA detection of Mtb-modified LDL (mtLDL) as a diagnostic tool for TB, which meets the WHO 2015 TPP criteria for acceptance of a rapid test. We will establish proof of concept that the mtLDL assay can distinguish active TB and latent TB in small volume blood samples from pediatric patients. Aim 1 is to calibrate mtLDL detection in the presence of possible interferents. Aim 2 is to establish and validation the mtLDL assay distinguishes between active disease and latent TB infection in children. We have a strong team of scientists engaged in TB diagnostics/therapeutics development working in collaboration with clinicians running clinical trials who are providing us excellent resources to fulfill the proposed aims. 11/15/2017 Stony Brook University LIBH image of external link icon Diagnostic assay Diagnosis of pediatric tuberculosis Available
Soluble Amylin Analogs for Co-formulation with Insulin Daniel Raleigh Diabetes has reached epidemic levels in the United States. The polypeptide hormone amylin normally plays an adaptive role in metabolism, but forms amyloid in type-2 diabetes which contributes to betacell dysfunction. Amylin is absent in type-1 diabetes. An amylin analog, Symlin, is approved by the FDA for the treatment of type-1 and type-2 diabetes and leads to improved glycemic control, however it suffers from poor solubility and cannot be co-formulated with insulin. We have developed a strategy for designing, non-toxic analogs of amylin which are considerably more soluble than Symlin. They are protected by two pending patents. We will develop amylin variants for co-formulation with insulin. We will: 1) test their co-formulation with insulin and, if necessary, redesign analogs with improved co-solubility; 2) test the stability of our analogs and, if needed, improve it, 3) confirm that they are nontoxic and, if needed, improve their bioactivity the targeted outcomes for the granting period are: a) to conduct critical measurements needed to take advantage of a licensing opportunity b) to be positioned to transition 3 top lead candidates from in vitro to in vivo testing and c) to improve the IP position of the products prior to commercialization. 11/15/2017 Stony Brook University LIBH image of external link icon Biologic drug Diabetes Melitus Available
Fast Hybrid Approach for Determination of Structure of TherapeuticProtein Complexes Dima Kozakov Therapeutic proteins, including antibodies, affibodies and other scaffolds have become promising drugs for treating cancer, infectious and cardiovascular diseases, inflammation and immune disorders. Whereas the standard method for development of high-affinity therapeutic proteins uses combinatorial libraries in various display platforms, recent studies demonstrate the power of rational design approaches that utilize computational docking methods to predict 3D structure of the complex between therapeutic proteins and their targets as a starting point for the next round of optimization. However, these studies also show that current methods need improvements. One of the promising strategies can be a combination of computational docking with low resolution data obtained from chemical crosslink experiments, which up to now had limited applications due to requirement of highly complicated protocols accessible to only few labs. During previous LIBH feasibility funding period, we have established possibility of streamlining the approach by 1) developing of novel ultrafast protein docking algorithm able to deal with crosslinking restraints using regular desktop. The work has been reported in PNAS, and Bioinformatics. 2) demonstrating feasibility of novel crosslink protocol to simplify identification of crosslink sites. Based on these results, the deliverable of the current POC proposal will be software package for determining structure of protein complex, using masspec crosslinking data, coupled with patented simple protocol for crosslinking, which is superior to the ones available on the market. 11/15/2017 Stony Brook University LIBH image of external link icon Research tool Cancer, infectious and cardiovascular diseases, inflammation and immune disorders Available
Non-Invasive Detection of Pancreatic Cancer Arie Kaufman Pancreatic cancer is a primary cause of cancer mortality, with extremely poor prognosis and overall five-year survival rate of only approximately 8%. Non-invasive early detection of pancreatic cysts could offer the opportunity to curtail the disease. We propose a novel approach for identifying, classifying, and visualizing pancreatic cysts from computed tomography (CT) imagery. Our proposed work builds upon our Virtual Pancreatography prototype for analyzing and visualizing CT pancreatic data. The proposed aims are: (1) develop and validate fully automatic segmentation of the pancreas and cysts using deep learning; (2) develop and validate improved cyst classification using deep learning; (3) develop an enhanced 3D visualization of pancreas and cyst features; and (4) integrate all components into a system with commercial grade software. Aims 1 and 2 will take six months each, aim 3 will take ten months, and aim 4 will occupy the last six months. Our segmentation and classification components will be delivered as independent modules or incorporated into the visualization interface to provide a unified end-to-end application. This application will be used by radiologists for non-invasive detection and analysis of pancreatic cancer. Our team has a proven record in developing new medical diagnosis techniques, most notably the virtual colonoscopy. 11/15/2017 Stony Brook University LIBH image of external link icon Diagnostic device Pancreatic cancer Available
Novel PEPCK metabolic inhibitors for cancer therapy Geoffrey Girnun N/A 01/01/2018 Stony Brook University LIBH image of external link icon Small molecule drug Colon cancer Available
Novel therapeutics against fungal infection diseases Maurizio Del Poeta The goal of this project is to discover and develop a new therapeutic(s) more potent than current antifungals for the treatment of invasive fungal infections. Among invasive fungal infections, cryptococcosis, candidiasis, and aspergillosis are the most life-threatening. The incidence of these infections has risen more than 14-fold over the last 20 years, with a mortality rate of 1,400,000/year. We recently discovered a fungal enzyme, ceramide synthase 1 (CerS1), essential for fungal growth at neutral, alkaline and acidic environments. Thus, a fungal mutant lacking CerS1 is not pathogenic in animal models because, upon infection, it cannot survive in host neutral (lung and other organs), alkaline (blood) and acidic (inflammatory tissue) environments. Thus, Cers1 is an ideal target for the development of new antifungals because any compound blocking CerS1 will be fungicidal. We have identified and optimized a high throughput assay that allows the screen for selective and specific inhibitors of fungal CerS1. Thus, we will screen our ChemBridge DIVERSet library for compounds inhibiting fungal CerS1 but not human CerS and select the best hit molecule(s) to move forward for medicinal chemistry and preclinical studies. We do have the experience and expertise to perform these studies. 11/15/2017 Stony Brook University LIBH image of external link icon Small molecule drug Antifungal Technology licensed to small company
Novel therapeutics for MDR Pseudomonas aeruginosa Fereidoon Daryaee Novel therapeutics are urgently needed to treat diseases caused by MDR strains of Pseudomonas aeruginosa. P. aeruginosa is responsible for ~10% of all hospital acquired infections, and drug resistance results in an increase in per-patient costs of &gt;$44,000. We will develop inhibitors of UDP-3-O-((R)-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (paLpxC), an enzyme which is essential for the viability and virulence of P. aeruginosa. Our novel approach will lead to paLpxC inhibitors that dissociate slowly from the target and that will have extended activity at low drug concentration so that they can be administered at lower doses, resulting in decreased side effects. Proprietary paLpxC inhibitors have already been developed with nM-pM potency, MIC values as low as 0.125 &Icirc;&frac14;g/ml and extended residence time on the target. In this REACH proposal we will synthesize additional analogs of our proprietary series that have increased affinity and/or residence time, and will determine the in vivo efficacy of selected compounds in a preclinical model of infection. The outcome of these studies will be to validate a mechanistic PK/PD model that integrates drug-target kinetics into predications of drug activity and to identify suitable proprietary chemical matter for optimization through funding mechanisms such as Phase I and Phase II STTR/SBIR grants. 11/15/2017 Stony Brook University LIBH image of external link icon Small molecule drug Nosocomial Pseudomonas infectins Available
High-Throughput connectomics using in-situ sequencing Alexander Vaughan Despite overwhelming interest, there is currently no efficient method to map the connectivity of individual neurons in the brain, nor to link the anatomy of individual neurons to their gene expression profile. We aim to meet this need through the commercialization of two technologies: MAPseq, a method that allows us to "map" the projections of individual neurons throughout the brain with massive throughput; and BCseq, a method allowing simultaneous recovery of neuronal projections, cell body location, and gene expression profiles. We intend to offer these services for two sets of customers: academic neuroscience researchers, and pharmaceutical partners. While there is strong interest in these techniques in both communities, the complexity of these techniques is a barrier for many researchers that can be met by a commercial service. Here, we propose to adapt existing protocols for both MAPseq and BCseq to improve throughput and reduce costs. As such, our milestones are focused on establishing concrete improvements in the cost or performance of our existing protocols. These efforts are spearheaded by Alexander Vaughan, Ph.D., currently Scientific Project Manager of the IARPA MICrONS project at CSHL, a multi-milliondollar project that uses MAPseq and BCseq technologies to recover synaptic connections throughout the brain. 11/15/2017 Cold Spring Harbor Laboratory LIBH image of external link icon Research tool N/A Available
A Synthetic Heparin Derivative that Targets Collagen to Repair Damaged Vasculature after Balloon Angioplasty Jason Albert Wertheim "There are an estimated 2.3 million percutaneous coronary interventions, PCIs (with angioplasty &Acirc;&plusmn; stent), performed annually in the US and EU5 countries. These procedures, in addition to ballon angioplasties of other vessels (e.g., renal, femoral and lower extremity arteries), typically require daily doses of systemic anticoagulation to prevent intravascular thrombosis at the site of balloon treatment. There is no targeted therapy that sequesters coagulant to injured coronary vasculature after PC I. Researchers at Northwestern University developed a heparin molecule that will bind to exposed collagen at the angioplasty site. The therapeutic product being developed is called collagen-binding peptide:Heparin or CBP:Heparin and functions based upon the injury mechanism observed during coronary angioplasty and stent placement. Initial, proof-of-concept studies show specific binding to collagen IV and clot reduction within vasculature and presence of heparin bound to collagen up to one week after administration. Targeting heparin to exposed collagen at the injured vessels may reduce or eliminate the need for repetitive, frequent (daily) doses of systemic anti-platelet agents typically required after PCI." 01/01/2018 Northwestern University NCAI-CC image of external link icon Small molecule drug Percutaneous Coronary Interventions (anti-coagulant) Option to license
Novel Small Molecule Therapeutic for Heat Failure Sathyamangla Prasad "Researchers at Cleveland clinic are in the process of developing a novel small molecule therapeutic to treat heart failure (HF). Heart failure is a multifactorial clinical syndrome associated with the inability to pump blood to the organs due to reduced contractile function, Beta blockers have been the mainstay of therapy, however the treatment does not ameliorate cardiac dysfunction; rather only serves to slow down the progression of heart failure. In addition, it is also clinically known that only about 30-40% of the HF patients respond to beta-blockers, and that non-responding patients have an average survival rate of only 5 years. Beta-adrenergic receptors regulate cardiac contractile function. Inactivation of beta-adrenergic receptors is a key molecular feature in HF. The goal of this project is to develop a small molecule therapeutic to restore that inactivated beta-adrenergic receptors, thereby improving cardiac function in HF patients. Preliminary data using a known small molecule probe has shown that this mechanism is feasible based on in vitro and in vivo efficacy models of HF. Based on the preliminary data from suing the probe compound the researchers have used structure based drug design techniques to design a series of compounds that have the potential to modulate the target. The investigators have picked a first set of most promising compounds that are currently being synthesized. After in vitro and in vivo testing othese compounds an SAR strategy will be developed to identify a lead compound to conduct lead optimization and preclnical development." 05/01/2018 Cleveland Clinic NCAI-CC image of external link icon Small molecule drug Heart Failure Available
GMP Vector Production for Gene Therapy for Sickle Cell Disease Punam Malik Sickle cell anemia (SCA) is one of the most common genetic defects, affecting the beta-globulin gene that results in production of a defective sickle hemoglobin (HbS). The disease affects over 90,000 Americans, with 2000 infants born with SCA every year. However, nearly 1000 babies are born daily with the disease in Africa. Therapeutic options are limited to a hematopoietic stem cell (HSC) transplant from a normal bone marrow donor. HSC transplant, however, is available only to 10-15% of patients who have matched normal sibling donors and is often associated with serious immune side effects. Fetal hemoglobin (HbF) produced during fetal life and the first 6-9 months of age, has strong anti-sickling properties and protects the infant from sickling complications in the first year of life. /indeed, SCA individuals with hereditary persistence of HbF into adulthood are similarly protected and remain asymptomatic. Genetic correction of autologus (self) bone marrow HSC with the huan gama-globulin gene that continues to express throughout life could permanently result in HF production in HbS-containing red blood cells, and prevent sickling. Researchers at CCHMC are currently evaluating an autologous gene-modified transplant process which requires much less supportive therapy, and thereby may allow transportability to many more institutions and even to resource poor countries where the majority of SCA patients are present. The project is to perform GMP production of vector for additional patients to support an ongoing Phase I/II clinical trial. This funding will allow us to sustain the momentum for completing this trial and demonstrate the potential for providing a one-time permanent correction of the sickle phenotype with a reduced intensity regiment. Completion of this pilot study, will help pave the way for a definitive study, licensure and commercialization of this technology. 05/01/2018 Cincinnati Children's Hospital Medical Center NCAI-CC image of external link icon Biologic drug Sickle Cell Disease Technology licensed to startup
A New Biological Therapy for Atrial Fibrillation Rishi Arora Atrial fibrillation (AF) is the most common heart rhythm disorder that affects &gt;3 million Americans and is a major cause of stroke. Since AF is primarily an agerelated disease, it is fast becoming an epidemic in a rapidly aging population. Unfortunately, current therapeutic approaches to AF &acirc; both pharmacological and ablation-based - are sub-optimal in patients with persistent AF. This is thought to be in part because current treatments do not target the fundamental, molecular mechanisms that cause AF. We propose a radically different approach to AF that will target one or more major molecular mechanisms underlying the development of the AF disease state. If successful, this approach stands to dramatically improve upon current therapeutic strategies for AF, and lead to a paradigm shift in the management of AF. Using technology developed at Northwestern University (NU), we propose an innovative, gene therapy strategy to target key molecular mechanisms that underlie the development of the AF disease state. The therapy comprises of one or more trans-genes targeted to the following key molecular mechanisms underlying AF: 1) Oxidative Stress (OS) and 2)Parasympathetic signaling. OS will be targeted with NOX2 shRNA. Parasympathetic signaling will be targeted by minigenes expressing G&Icirc;&plusmn;i + G&Icirc;&plusmn;o inhibitory peptides (1:1 combination). The specific goal of this proposal is to determine whether NOX2 shRNA and G&Icirc;&plusmn;i/o peptides &acirc; given singly or in combination &acirc; will reverse established AF substrate in a clinically relevant canine model of AF (rapid atrial pacing model). The trans-gene(s) most successful at reversing AF substrate will be advanced into clinical testing. Our long term goal is to develop a new, mechanism-guided therapy for AF that has at least 70% efficacy in patients with persistent AF and thereby has the potential to substantially reduce the morbidity and mortality associated with AF. AF is a $2 billion + market, and this technology is expected to significantly improve upon the success of current pharmacological and ablation strategies in treating AF. 05/01/2018 Northwestern University NCAI-CC image of external link icon Biologic drug Artrial Fibrillation (AF) Technology licensed to startup
T Cell Reactivation Immunotherapy for Tumors David Masopust The proposed product is a peptide therapy that reactivates microbe-specific T cells within tumors to induce immune-stimulatory and anti-tumor effects. 02/01/2018 University of Minnesota MN-REACH image of external link icon Biologic drug Solid tumors Available
Directional Coordinated Reset Deep Brain Stimulation and A Novel Stimulation Strategy Jerrold Vitek The proposed technology is a novel and simplified deep brain stimulation algorithm for treatment of Parkinson's disease that increases the battery life and reduces the incidence of side effects associated with higher currents that may spread to adjacent brain regions. 02/01/2018 University of Minnesota MN-REACH image of external link icon Therapeutic device Parkinson's disease Available
Translation of novel fluoroquinolones with anti-colon cancer activity Hiroshi Hiasa The proposed product is a novel drug candidate that is as effective as approved topoisomerase inhibitors for colon cancer with a more desirable safety profile. 02/01/2018 University of Minnesota MN-REACH image of external link icon Small molecule drug Colon cancer Available
DBS as a brain tumor treatment modality Clark Chen The proposed product is an implanted brain electrode as &acirc;multi-drug&acirc; with patented stimulation parameters designed to disrupt distinct cellular processes required for glioblastoma growth. 04/01/2018 University of Minnesota MN-REACH image of external link icon Therapeutic device Glioblastoma multiforme Available
Detecting aerobic glycolysis in pre-invasive breast cancer by a positional isotopic labeling-based tgtd. metabolomics mthd. DaQing Yang The proposed diagnostic will be used for detection of pre-invasive breast cancer and can differentiate them from non-invasive breast tumors and suspicious lumps/lesions, which will significantly reduce the number of patients who need breast biopsy procedures. This test will additionally be used to monitor the therapeutic response in patients who have undergone chemo- or radiotherapy treatment. 01/01/2018 University of Minnesota MN-REACH image of external link icon Diagnostic device Breast cancer Technology licensed to startup
Controlling Neuropathic Pain and Opioid Addiction By Novel Non-Opioid Analgesics Carolyn Fairbanks Neuropathic pain affects over 26 million patients in the US. The current treatment methods of anticonvulsants, antidepressants and opioids only provide satisfactory pain relief in 30-40% of patients. The proposed drug leverages neuroplasticity modulation in order to slow or halt the progression of neuropathic pain without the side effects of the current treatments or addiction concerns of opioids. 01/01/2018 University of Minnesota MN-REACH image of external link icon Small molecule drug Pain Available
A novel method to treat the systemic inflammatory response syndrome (SIRS) J. Brian McAlvin We have developed highly-selective blood-filtering devices that are capable of filtering of individual, harmful molecules from the blood of patients rendered critically ill by the systemic inflammatory response syndrome (SIRS). Antibody modified conduits(AMCs) are modified to remove specific circulating harmful molecules, and are incorporated within existing extracorporeal systems (e.g. dialysis, ECMO, plasma exchange and apheresis circuits). Each AMC filters a single, unique molecule. AMC combinations are chosen to selectively remove specific, deleterious molecules as they arise and are exchanged with new AMCs as host molecule expression changes. These temporally controlled, targeted manipulations of the introduce a novel treatment paradigm for SIRS. SIRS is the underlying mechanism for a variety of common critical illnesses including sepsis, ARDS, pancreatitis, trauma, burns and SIRS triggered by cardiopulmonary bypass surgery. Users of this device would be critically ill patients in the ICU or operating room with any disease for which the underlying mechanism is SIRS. Here, we use sepsis as the model disease in which to study the function of AMCs. Users of the device would be critically ill patients with SIRS resulting in multi-organ injury. 02/01/2018 Boston Children's Hospital B-BIC image of external link icon Therapeutic device Systemic inflammatory response syndrome Available
Fully humanized anti-DEpR antibody therapy for acute lung injury (ALI)/Acute Respiratory Distress Syndrome (ARDS) Nelson Ruiz-Opazo The feed-forward progression of acute lung injury (ALI) towards acute respiratory distress syndrome (ARDS) and multi-organ failure (MOF) remains a high unmet need with ~200,000 cases per year (US) affecting both young and old. Mortality remains high at 40% despite intensive care supportive interventions. To date, there is no curative-intent therapy despite research efforts. Regardless of etiology, neutrophils play key pathogenic roles, even in neutropenic patients, however, prior attempts at inhibiting neutrophils have not succeeded. To address these clinical and technological needs, we propose to study our fully humanized S228P hinge-stabilized IgG4 antibody, that inhibits the dual endothelin1/signal peptide receptor, DEspR, 6g8-humab, as a novel therapy that has the potential to stop the feed-forward progression of ALI-ARDS-MOF driven by self-amplifying, excessive activated-neutrophil injury responses. This therapeutic-target hypothesis is supported by data that 1-validate the target: increased DEspR expression on activated neutrophils, not present on quiescent neutrophils and normal lung tissue; 2-elucidate the proposed mechanism of action: DEspR inhibition decreases survival of activated neutrophils, and 3-validate pilot in vivo efficacy of the prototype anti-DEspR murine mAb (mumab) in an LPS-induced rat model of ARDS-MOF-early death tracking sepsis-related hemorrhagic encephalopathy. Here, we propose the following. Aim1. Demonstrate that anti-DEspR 6g8-humab can stop or decrease ALI-ARDS-MOF progression thus increasing survival in a rat model of LPS-induced, sepsis-related ALI/ARDS. Aim2. Demonstrate lung target engagement of 6g8-humab and mechanism-based bioeffects in treated rats compared to isotype mock-treated ALI/ARDS-rats. Data obtained will inform Go/NoGo decision on 6g8-humab as potential novel first-in-class therapy for ALI-ARDS-MOF. 01/01/2018 Boston University B-BIC image of external link icon Biologic drug Acute Lung Injury / Acute Respiratory Distress Syndrome Available
Novel Prostate Cancer Drug, BKI-1553 Wesley Van Voorhis Treatment of castration resistant adenocarcinoma of the prostate remains an unmet medical need. Current 2nd generation drugs used for metastatic prostate cancer (PC), abiraterone, apalutamide, and enzalutamide have extended lifespan only 4 months compared to 1st generation androgen receptor targeted therapies. Over 80% of PC continue to express androgen receptor (AR+) after these therapies, but have lost responsiveness to androgen receptor targeted therapies, and are termed &acirc;castrate-resistant prostate cancer&acirc; (CRPC). This resistance to current PC drugs occurs annually in over 20,000 individuals with metastatic AR+ CRPC in the USA, creating a medical need for a new drug. We found that the bumped-kinase inhibitor BKI-1553 is effective against AR+ PC in vitro and in mouse human AR+ PC xenograft models. BKI-1553 causes growth arrest and cell death in responsive PC models. Treatment in mouse CRPC xenograft models is accomplished with as little as 20 mg/kg BKI-1553, given orally only three times a week. BKI-1553 pharmacology (PK) has been studied in mice, rats, dogs, calves, sheep, and monkeys and behaves predictably with allometric scaling, suggesting human dose estimates will be reliable. BKI-1553 has been studied in vitro and in vivo. Toxicology and PK assays demonstrate favorable safety and PK parameters consistent with a pre-clinical drug candidate. Several lines of evidence are consistent with the hypothesis that treatment with BKI-1553, leads to Selective Glycolysis Inhibition in only prostate cancer cell lines. This is a novel mechanism of action, but also brings to fulfillment the 100 year-old Nobel Prize winning discovery of Otto Warburg, that cancer cell lines use glycolysis to replicate more than mitochondrial oxidative respiration. We have renamed the compound to SGI-1553, for this novel mechanism of action. 10/26/2020 University of Washington WE-REACH Small Molecule Drug Cancer Available
First-in-Class Pan-TAM/GAS6 Tyrosine Kinase Inhibitors for Cancer Therapy Raymond Birge The overarching goal of this project is the development of a small molecule inhibitor that targets the Tyro3, Axl, and Mertk receptors (TAMs, collectively pan-TAM) as a novel, disease-modifying treatment for patients with triple negative breast cancer (TNBC). The applicants envision first-in-class treatments for cancer therapy, either as stand-alone therapeutics or in combination with the latest generation of standard-of-care treatments such as immuno-oncology (IO) checkpoint inhibitors. The project team has pursued an innovative approach and are developing extracellular small molecule inhibitors against TAM/GAS6 complex that are anticipated to possess improved specificity and fewer off-target effects compared to conventional Tyrosine Kinase Inhibitors (TKIs). The project focuses on proof-of-concept preclinical evaluation of a series of small molecule compounds to develop a pan-TAM inhibitor clinical candidate for TNBC. The team will work to achieve three proposed milestones over two years: 1. Lead optimization of pan-TAM inhibitors toward identification of a clinical candidate for TNBC (iterative), 2. Demonstrate the efficacy of optimized pan-TAM inhibitors in vitro and in vivo (mouse) model, and 3. Demonstrate that pan-TAM inhibitor compounds exhibit acceptable pharmacokinetics (PK) and safety/toxicity profiles. 07/01/2020 Rutgers University ROI image of external link icon Small Molecule Drug Small molecule inhibitors - RU300 compound series Cancer, Triple Negative Breast Cancer Available Pragati Sharma
iSense: A First-in-Class Therapy for Insufficient Pupil Dilation Cristos Ifantides Reformulating dexmedetomidine into an eye drop to treat patients whose eyes do not dilate well. This eye drop integrates into standard pre-treatment procedures prior to cataract surgery. 07/01/2020 University of Colorado Denver CAMC image of external link icon Small Molecule Drug Ophthalmology Available
LPL activators as novel therapeutics for AD Kimberly Bruce Validated a novel target, lipoprotein lipase, involved in neuronal development and maintenance. Team is developing LPL activators for treating neurodegenerative conditions. 07/01/2020 University of Colorado Denver CAMC image of external link icon Small Molecule Drug Neurology Available
Oral Biofilm Disruption and Selective Inhibition of S.mutans Biofilms Devatha Nair Carrying out toxicity and biocompatibility studies of a novel bio-organic dental coating. The novelty of the coating is that it mechanically disrupts cariogenic-biofilm formation via visible light activation. 07/01/2020 University of Colorado Denver CAMC image of external link icon Other Dentistry Available
Multifunctional Nanoclusters for Detection and Treatment of Bladder Cancer Tom Flaig Developing a &acirc;theranostic&acirc; nanoparticle to diagnose and treat superficial EGFR+ bladder cancer. These nanoparticles, which are coated with gold nanorods, will target cancer lesions with anti-EGFR mAb. The nanorods will ablate lesions upon light stimulation. 07/01/2020 University of Colorado Denver CAMC image of external link icon Therapeutic Device Cancer Available
IL2-CCR4 Bispecific Immunotoxin Targeting Cutaneuous T-Cell Lymphoma Zhirui Wang Complete efficacy and PK studies of a diphtheria toxin IL2-CCR4 immunotoxin for cutaneous T-cell lymphoma and potentially other Treg-IL2 cancers. 07/01/2020 University of Colorado Denver CAMC image of external link icon Biologic Drug Cancer Available
Repositioning neurokinin-1 receptor (NK-1R) antagonists as antiviral agents against human herpesviruses Maria Nagel Repurposing NK-1R antagonists as antiviral agents for neuronal infection of varicella zoster virus. Zoster vaccines do not support neuronal infection or patient&acirc;s under 50 y/o. 07/01/2020 University of Colorado Denver CAMC image of external link icon Research Tool Infection Control Available
Developing a small, portable CT scanner for brain scans. The CT scanner uses flat panel X-ray detectors as well as scatter mitigation and associated algorithms. Cem Altuntas Developing a small, portable CT scanner for brain scans. The CT scanner uses flat panel X-ray detectors as well as scatter mitigation and associated algorithms. 07/01/2020 University of Colorado Denver CAMC image of external link icon Diagnostic Device Medical Imaging Available
Methods for understanding functional heterogeneity among single cells Jay Hesselberth Developing a kit that can measure functional activity of various enzyme classes or specific target at the single cell level. Technology provides actual functional activity in a single cell workflow. 07/01/2020 University of Colorado Denver CAMC image of external link icon Research Tool Cancer Available
Novel Inhibitors of trimethylamine lyase for treatment of rheumatoid arthritis Kristi Kuhn Developing novel small molecule therapeutics for rheumatoid arthritis. This is a novel non-immunosuppressive therapeutic strategy by drugging the human microbiome. 07/01/2020 University of Colorado Denver CAMC image of external link icon Small Molecule Drug Immunology Available
Treatments for tuberculosis and non-tuberculous mycobacterial lung infections: dual-targeted rifamycin-AAP conjugates (RifaAAPs) Richard Ebright We are developing a novel class of dual-targeted rifampin-AAP conjugates, "RifaAAPs," comprising the core pharmacophore of rifampin (Rif; first-line anti-TB drug that binds to the mycobacterial RNA polymerase active center and sterically blocks RNA synthesis) covalently linked to an N&amp;#945;-aroyl-N-aryl-phenylalaninamide (AAP; synthetic anti-TB agent that binds to a different site on mycobacterial RNA polymerase and allosterically blocks RNA synthesis). RifaAAPs inhibit mycobacterial RNA polymerase through two different binding sites (the Rif and AAP binding sites) and two different mechanisms (the Rif and AAP mechanisms). As a result, RifaAAPs are able to overcome Rif&amp;#8208;resistance and are able to overcome to AAP&amp;#8208;resistance. As a further result, RifaAAPs exhibit much lower&amp;#8208;&amp;#8208;orders of magnitude lower&amp;#8208;&amp;#8208;resistance emergence than Rif and AAP (with RifaAAP-resistance requiring a rare double mutational hit that alters both the Rif site and the AAP site, in contrast to Rif-resistance and AAP&amp;#8208;resistance, each of which requires only a single mutational hit that alters the Rif site or the AAP site). RifaAAPs will provide (1) a shorter treatment duration and a higher treatment success rate for treatment of drug&amp;#8208;susceptible, drug-resistant, multi-drug-resistant, and extensively-drug-resistant TB, and (2) a shorter treatment duration and a higher treatment success rate for treatment of nontuberculous mycobacterial lung infections. 11/13/2020 Rutgers University ROI image of external link icon Small Molecule Drug Novel, first-in-class, orally-available drugs (Rifamycin-AAP conjugates) efficacious against tuberculosis and non-tuberculous mycobacterial lung infections Antimicrobial Products, TB and Non-TB Mycobacterial Lung Infection Available Pragati Sharma
EigenSciope: Smartphone-based Endoscopy Randall Bly Flexible laryngoscopy is a common procedure in Otolaryngolgy used to evaluate the larynx yet is limited to being performed in specialized offices using large, expensive pieces of equipment called towers. This results in poor access to this necessary diagnostic examination as the tower sequesters the video data. Our solution provides all the capabilites of the tower onto a smartphone making flexible laryngoscopy drastically more accessible and replaces the tower for a fraction of the cost. 10/01/2020 University of Washington WE-REACH image of external link icon Diagnostic Device Gastroenterology Available
Intubating Laryngeal Mask Airway for Neonates Taylor Sawyer Tracheal intubation is one of the most commonly performed procedures in neonatal medicine, with an estimated 500,000 procedures performed each year. The device most commonly used for neonatal intubation is the laryngoscope. Using a laryngoscopy, only 50% of neonatal intubations are successful on the first attempt, adverse events occur 20% of the time, and up to 50% of babies experience severe drops in oxygen levels that could cause brain damage. Failed intubation attempts using direct laryngoscopy have been associated with severe brain hemorrhages and neurodevelopmental impairment in premature infants. These facts have led some to call intubation using direct laryngoscopy "one of the most dangerous procedures in neonatal medicine." Alternatives to the laryngoscope exist, but none have been widely adopted because they are more complicated and more technically challenging than the laryngoscope. Therefore, innovating a safer way to perform neonatal intubation is an urgent need. With prior support from the UW CoMotion Innovation Fund, the PI has developed a patent-pending, Class 1-510 (k) exempt, intubating laryngeal mask airway for neonates. The innovative device makes intubation easier and safer than laryngoscopy. With WE-REACH funding, we will accelerate the commercialization of the device into a commercial product. Specifically, we will advance prototype development from our current proof of concept prototype (TRL 3-4) to a feasibility prototype (TRL 6). To do this, we will meet the following milestones by the completion of the project.1.FRAME: Establish product and project constraints and review predicate products andprototypes.2.CREATE: Engineer two feasibility prototypes from components and assemblies that meet quality system requirements (QSR) and good manufacturing practices(GMP).3.TEST: Test the feasibility prototype against product requirements and design intent in a laboratory environment using a neonatalmanikin.Completing the above milestones will position the device to proceed down one of two future commercialization strategies: &acirc;Early-exit&acirc; commercialization with a final goal of IP licensing, or &acirc;late-exit&acirc; commercialization with a final goal to create a small business startup to develop, manufacture, and sell the device with follow on funding through an NIH STTR grant. 10/01/2020 University of Washington WE-REACH image of external link icon Therapeutic Device Pulmonology Available
Targeted Nanoparticle Therapeutic for the Treatment of Hematological Cancers Bret Ulery Hematological cancers are malignancies of blood-forming tissues for which over 170,000 new diagnoses are expected this year according to the Leukemia &amp; Lymphoma Society. The most common hematological cancer is lymphoma which is characterized by the development of tumor masses in the lymph nodes. The most frequently diagnosed type of lymphoma is the non-Hodgkin&acirc;s subtype, designated diffuse large B cell lymphoma (DLBCL). Though frontline treatment consisting of infusion chemotherapy sometimes supplemented with radiation or intrathecal chemotherapy is quite effective in treating DLBCL, relapse or refractory disease occurs in 30-50% of all patients, and is associated with a very poor prognosis. There is a significant need for a new treatment, and while a variety of promising therapeutics are currently being developed to improve frontline and/or intensification treatment approaches, they possess considerable drawbacks. To address this unmet need, the team of translational researchers has created a targeted nanoparticle-based composite drug delivery system that is envisioned to be a safer and more efficacious alternative treatment modality for difficult to treat, relapsed or refractory DLBCL. The novel therapeutic will also have the potential to be expanded into an adjunct to or replacement for standard of care R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, and predisone) therapy in the future. Additionally, DLBCL is one of the most common and deadliest malignancies in canines, presenting a comprehensive pathway to translation in both companion animals and humans. 09/01/2020 University of Missouri Columbia MBArC image of external link icon Small Molecule Drug Cancer Available
Intravenous Antibiotics for the Treatment of Hospital Acquired Pneumonia (HAP) Resistant to Conventional Medications George Gokel Antimicrobial resistance is a major healthcare concern as identified by the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). Hospital acquired infections have a high financial burden on the healthcare system and contribute significantly to inpatient morbidity and mortality in the United States. One such hospital acquired infection is Hospital Acquired Pneumonia and Ventilator Associated Pneumonia (HAP/VAP) that affects over 350,000 patients annually with a primary target market of approximately $200 Million in the US. HAP/VAP that are caused by multidrug resistant (MDR) Gram-Negative bacteria (GNB), are difficult to treat and lack effective first line therapies. To address this unmet need, the team is developing a non-resistant, broad-spectrum combination antibiotic that can be administered once-a-day intravenously to hospitalized patients suffering from HAP/VAP. The innovation is in the new adjuvant that allows for passage of an antibiotic into the bacteria and inhibition of the bacterial resistance mechanism. The adjuvant also holds promise as a platform as it can be combined with multiple different antibiotics for the treatment of other multidrug resistant infections. This novel therapy has the potential to be fast-acting and effective, thereby benefiting patients and saving lives. 09/01/2020 University of Missouri St. Louis MBArC image of external link icon Other Pulmonology Available
Fistula Closure Device Stephen Waller A fistula is a communication between two hollow or tubular organs. While various types of fistulas can develop inside the human body, the most common and problematic is the enterocutaneous fistula (ECF), an abnormal communication between the small or large bowel and the skin. More than 71,000 hospitalizations for enteric fistulas occur yearly in the US. Common causes of ECF formation include surgery, inflammatory bowel disease (e.g. Crohn&acirc;s disease), trauma, malignancy and foreign body. The associated mortality rate is substantial (6-33%). Estimates also suggest that the development of an ECF can increase ICU length of stay (LOS) nearly 4-fold and the hospital LOS 5-fold. Hospital costs can increase accordingly. While therapeutic options are limited, medical devices such as clips, plugs and fibrin-based sealants have very low success rates. Conservative therapy that includes withholding of food along with intravenous delivery of fluids, nutrition and antibiotics for many weeks to months is prescribed initially to nearly all patients. However, it fails in 70-80% of cases. Surgical intervention is typically the treatment of choice when the fistula fails to close, however, 14-34% of those who undergo a fistula takedown surgery develop a new fistula. To address this widespread clinical problem, the team plans to develop a non-surgical intervention that can effectively close fistulas. Cyanoacrylate (&acirc;superglue&acirc;)-based adhesives like Trufill&Acirc;&reg; are approved for use of wound closure. However, the inability to control these adhesives after their injection through a delivery device (i.e. catheter) has substantially limited their use internally. The proposed device, Fistula Fix, offers precise delivery and control of these powerful tissue adhesives to achieve closure of many fistula types that currently have no effective treatment options. Fistula Fix is designed to be a non-surgical, catheter-based procedure that has the potential to offer accurate control and placement of adhesive accomplished by mixing a proprietary magnetic nanoparticle with the cyanoacrylate tissue adhesive, and controlling the position of the adhesive/nanoparticle solution with an electromagnetic field near the end of the delivery catheter until the adhesive polymerizes. 09/01/2020 University of Kansas Medical Center MBArC image of external link icon Other Platform Technology Available
Administration of Human Mesenchymal Stem Cells as a Late Acting Therapeutic Against Acetaminophen Induced Liver Injury Anup Ramachandran Acetaminophen (APAP), one of the most commonly used analgesics worldwide, is present in many prescription drugs and over-the-counter medicines. Though safe at therapeutic doses, APAP overdose induces liver cell death, ultimately compromising liver function, and resulting in acute liver failure. It is the most common cause of acute liver failure in the United States and leads to around 56,000 emergency room visits, 30,000 hospital admissions and 500 deaths annually. The only FDA approved treatment for an APAP overdose is N-acetyl-cysteine (NAC), which is most effective when administered early after APAP consumption. However, patients typically present much later to the clinic once symptoms are evident, by which time liver injury is already progressed and effectiveness of NAC is diminished. Thus, there is a critical need for a late-acting therapeutic option which, when administered in the clinic, could prevent development of acute liver failure even in patients with ongoing liver injury. The proposed product, MSCTC-0010, being developed by the Midwest Stem Cell Therapy Center, is one such intervention. In targeting liver regeneration, it is uniquely different from the standard of care, NAC, and has promising therapeutic potential. 09/01/2020 University of Kansas Medical Center MBArC image of external link icon Biologic Drug Liver Available
Rapid Trocar Site Closure Device Daniel Metzinger Closure of the abdominal wall during laparoscopic surgery is becoming increasingly difficult due to the growing population of obese patients and the use of larger cameras and trocars in robotic surgery. Globally in 2018, there were nearly 15 million laparoscopic procedures performed, with the US accounting for nearly 32% of all cases. Our team has developed a Trocar Site Closure device that prevents herniation by &acirc;blocking the hole&acirc; in the abdominal wall to prevent herniation. Our device is biodegradable, rapidly deployed, straightforward and easy to use regardless of patient size and allows the abdominal wall and fascial layer to heal naturally. The initial design has been tested in multiple cadaver studies and 1 chronic REACH Common Application 2 porcine (7 day) study, and based on those results, our team has arrived on the final design based on current iterations and manufacturability analysis. The novel device is protected by 1 issued patent and 1 pending PCT application. KYNETIC funds will be critical to drive the device to the market to address a significant and growing unmet clinical need to prevent hernia formation following laparoscopic surgery. Funding will be used to complete production of the final device and demonstrate efficacy in human cadaver and chronic porcine studies. Additional tranches of funding will be used to finalize the design of the delivery handle and demonstrate safety and efficacy in a chronic porcine model. The team is led by a GYN-Oncology surgeon with significant expertise in da Vinci Robotic Surgery, having performed more than 2,000 successful robotic procedures who knows firsthand the critical need for this device. The team also includes engineering expertise and is supported by an external medical device contract research organization. 01/01/2021 University of Louisville KYNETIC image of external link icon Therapeutic Device Wound Healing Available
Novel compounds for diagnosing, treating, and monitoring triple negative breast cancer Lindsay Calderon Triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancer cases and has the highest mortality and reoccurrence rates five years after diagnosis than any other form. Of utmost concern, TNBC is regarded as the most prevalent (42-56%) form in young women aged 20-34 years. Despite recent advances in breast cancer treatment, therapies for TNBC are scarce and inefficient, due to the lack of hormone receptor expression. As a result of the difficult to treat nature of TNBC, we have focused our research on designing a combinational diagnostic and therapeutic approach. We developed novel compounds (99mTc/186/188Re-LHRH) for better detection, therapy monitoring, and reoccurrence identification. Our radionuclides will detect the formation of in-situ reoccurrence earlier and more accurately than currently used technologies. Once tumor cells have been identified, our targeting compound (Pt-Mal-LHRH) shows increased selectivity and efficacy towards TNBC compared to other platinum-based chemotherapeutic agents. This technological advancement will increase the uptake of chemotherapeutics in cancer cells, resulting in tumor regression of TNBC. Both our chemotherapeutic and diagnostic agents have been shown to improve upon the limitations of the existing clinically used agents in-vitro and in-vivo. Our project goal is to perform in-vivo studies needed prior to application to the FDA and clinical trials. We have a highly capable team with backgrounds in drug development, compound synthesis, and pharmacology to advance this clinical need of a combinational therapeutic and diagnostic approach to help save patients afflicted with TNBC. 01/01/2021 Eastern Kentucky University KYNETIC image of external link icon Other Cancer Available
Developing BMPR2 Inhibitors and Methods of Trating Cancer and Cognitive Defects John Langenfeld Aberrant expression of bone morphogenetic proteins (BMP) has been shown to promote age-related diseases including cancer and Alzheimers disease. Our group has developed small molecular inhibitors targeting a BMP receptor that has never been targeted before. Our goal is to develop this novel class of compounds into a drug for the treatment of cancer and Alzheimers disease. Description: The main treatment for lung cancer today is chemotherapeutics such as Taxol combined with cisplatin. Approximately 85% of patients diagnosed with lung cancer will succumb to their disease despite treatment. Approximately 1.8 million people worldwide per year have advanced disease requiring a cancer therapeutic. The BMP receptor identified in our studies represent a novel target to treat lung and other carcinomas. Our unique BMP receptor inhibitors significantly suppress the expression of several proteins known to promote the growth and survival of cancer cells. Our BMP inhibitors represent a novel approach to treat cancer. Additionally, several mice studies have established that inhibition of BMP signaling in aging mice stimulates neural stem cells that normally reside in the brain to differentiate into mature functioning neurons which enhance cognition. The ability to regenerate new neurons in the brain would represent a novel treatment approach for Alzheimers disease and other related neurodegenerative diseases. Worldwide, approximately 40 million people have Alzheimers disease and this number is expected to rise to 120 million by 2050, demonstrating the need for novel therapies. Market Applications: Cancer therapeutic, Neuroregeneration for neurodegenerative disorders. 09/01/2020 Rutgers University ROI image of external link icon Small Molecule Drug Small molecule BMPR2 (Bone Morphogenic Protein Receptor 2) Inhibitors for cancer and Alzheimer's Disease Cancer, Neurology, Alzheimer's Disease Available Pragati Sharma
RU001-CAR-NK Immunotherapy for Hepatocellular Carcinoma Dongfang Liu This project is focused on developing an 'off-the-shelf' CAR-NK cells based immunotherapy for hepatocellular carcinoma (HCC). Globally, there are 800,000 new cases of HCC per year. Treatments are marginally effective today. By re-engineering NK cells to target the specific HCC cell marker CD147, and to thereby kill the HCC effectively and safely, this therapeutic solution is expected to circumvent the inevitable toxicity (GvHD and CRS) of the CAR-T therapy. The workplan includes in vivo toxicity testing by an accomplished team of immune cell biology experts and clinical pathologists. 09/01/2020 Rutgers University ROI image of external link icon Biologic Drug CAR-NK cells for solid tumors Cancer, Immunology, Liver Available Pragati Sharma
Development of a Cryptococcus vaccine against invasive fungal infections Chaoyang Xue Invasive fungal infections kill over 1.5 million people annually and constitute a rising and lethal threat to patients due to increased populations with immunodeficiency. Currently, the standard of care is limited to only three classes of antifungal drugs, and no fungal vaccine in clinical use. In this application, we propose to develop the first fungal vaccine that will protect risk populations against cryptococcosis and other deadly invasive fungal infections. We will determine the therapeutic value of the vaccine, optimize its patient administration methods, and identify the effective adjuvant to optimize the vaccine for further commercialization. We expect to develop a vaccine product in animal models that has both prophylactic and therapeutic value against fungal infections. The product will be ready for the pre-preclinical IND discussion with FDA at the end of this funding period. To archive our goal, we have assembled a highly collaborative team with complementary research skills and knowledge in fungal biology, immunology and product commercialization to carry out this project. 12/01/2020 Rutgers University ROI image of external link icon Biologic Drug Heat-Killed fbp1 Vaccine Infection control, Antimicrobial Products Available Pragati Sharma
Surface functionalization against microbial infections and biofilms Enver Izgu 12/01/2020 Rutgers University ROI image of external link icon Other No Disease or Organ Indication (platform technology) Available Pragati Sharma
CD6-targeted antibody-drug conjugate as a new drug for GVHD Feng Lin Graft-versus-host disease (GVHD) is a common complication that occurs after allogeneic bone marrow transplantation. GVHD damages multiple organs and deteriorates patient life quality with a mortality of approximately 50%. High-dose steroids are the current first line of treatment but it causes severe side effects. Many patients are also refractory to this therapy and have a poor prognosis. We have developed a CD6-targeted antibody drug conjugate (ADC) that holds promise as a new drug for GVHD. In this application, we propose to achieve three milestones to establish the potential of the ADC as a new drug for GVHD both in vitro and in vivo in a pre-clinical model of GVHD. The successful completion of this project will allow us to prepare a competitive STTR application to the NIHLB to further develop this potential new drug for GVHD, and possibly, for other similar T cell-mediated diseases. 10/01/2020 Cleveland Clinic NCAI-CC image of external link icon Therapeutic device Blood Available
Identification of a novel therapeutic to treat Abdominal Aortic Aneurysms Shaun Stauffer Abdominal aortic aneurysm (AAA) is a common disease that effects every population. AAA occurs when the abdominal aorta wall becomes weakened resulting in focal enlargement of the blood vessel with fatal consequences of aortic rupture. AAA treatment requires surgery when the aneurysm reaches a critical size. Non-surgical medical therapies for AAA have never been discovered. We found a new platelet receptor, Olfactory Receptor 2L13 (OR2L13) that appears to suppress AAA growth in mice when stimulated by drugs. Circulating platelets become reactive in patients with AAA as blood moves from steady laminar flow to a disturbed (D-flow) environment of aneurysmal arteries. Platelets therefore are biomechanically activated by D-flow in AAA. We evaluated ~2M patients in an administrative database and discovered anti-platelet drugs may suppress AAA growth. The ultimate goal of the project is to develop a non-surgical option for patients with AAA using platelet OR2L13 as a druggable target. 10/01/2020 Cleveland Clinic NCAI-CC image of external link icon Other Blood Available
TraumaChek: A Field-deployable Dielectric Coagulometer for Comprehensive Assessment of Trauma-induced Coagulopathy (TIC) Anirban Sen Gupta TraumaChekTM is a miniaturized, multichannel, portable, handheld blood coagulation analyzer for early, rapid, and comprehensive assessment of trauma-induced coagulopathy to guide hemorrhage control, transfusion, and resuscitative management of trauma at the point-of-injury by first responders and at the point-of-care by hospital clinicians. 10/01/2020 Case Western Reserve University NCAI-CC image of external link icon Diagnostic device Blood Available
Multi-modal photonic guidance for radiofrequency ablation therapy of atrial fibrillation Andrew Rollins AF impacts 2.7-6.1 million people worldwide and is expected to quadruple in the next three decades. RFA therapy has become a standard of care for the treatment of AF, but multiple treatments are usually required due to insufficient lesion quality and lack of target tissue information. We propose to provide direct tissue information during the procedure by incorporating multi-modal optical sensing at the RFA catheter tip. 10/01/2020 Case Western Reserve University NCAI-CC image of external link icon Research tool Cardiovascular Available
Baroreflex Activation for the Treatment of Refractory Hypertension Dustin Tyler The proposed technology would employ a device-based approach to treat patients suffering from high blood pressure who are not responding to medications. High blood pressure is a serious chronic condition and increasing numbers of patients here and world-wide are not getting needed benefit from medications thereby increasing the risk for vascular disease, stroke, heart attacks, and kidney disease. These patients need a viable alternative to medication based treatment and currently there is none&acirc;the proposed technology seeks to address this with a surgically implanted device. 10/01/2020 Case Western Reserve University NCAI-CC image of external link icon Diagnostic device Cardiovascular Available
Identification of a Novel Inhaled Therapeutics to Treat Idiopathic Pulmonary Fibrosis (IPF) Thaddeus Stappenbeck Idiopathic pulmonary fibrosis is a highly heterogeneous and lethal pathological process with few therapeutic options. Currently there are two FDA approved drugs and neither of them provide a cure and have several serious side effects and patients still experience a progression in fibrosis leading to decreased adherence to treatment. Plasminogen Activation Inhibitor-1 (PAI-1) is an endogenous inhibitor of tissue and urokinase plasminogen activator (tPA and uPA), regulating fibrinolysis and wound healing. Studies in mice that support a role for PAI-1 in lung fibrogenesis include transgenic mice that overproduce PAI-1 and develop an accumulation of excessive collagen following a fibrotic insult. Conversely, mice with targeted PAI-1 gene deletion are resistant to lung fibrosis and have improved survival following lung injury. This project would provide a small molecule weight novel therapeutic acting on plasminogen activator inhibitor 1 (PAI-1) that has efficacy in mice models that mimic features of IPF. If successful, we plan to deliver this therapeutic at the disease site, via an inhaled formulation. Currently marketed drugs or compounds that are in clinical trials do not target PAI-1 and those treatment options are thus far suboptimal. 10/01/2020 Cleveland Clinic NCAI-CC image of external link icon Therapeutic device Lung Available
Development of a Solution for the Preservation and Ex Situ Perfusion of Vascularized Composite Allografts Bohdan Pomahac Effective preservation of vascularized composite allografts (VCA; i.e. extremities, facial allografts, etc.) could beneficially impact the lives of millions worldwide. A large impediment to advancement of tissue transplantation and replantation is the lack of efficient delivery of effective tissue preservation. Short allowable ischemic time often limits the geographic location of recipients. Skeletal muscle has the shortest allowable ischemia time among transplantable organs (2 hours only, without cooling). In solid organ transplantation (SOT) and VCA ischemia-reperfusion injury still represents a bottleneck for the effective preservation of tissues. Time constraints have been eased by hypothermic machine perfusion (MP). Controlled continuous perfusion offers a number of advantages over the static cold storage method in several ways: maintenance of the patency of the vascular bed, continuous supply of nutrients and oxygen to support metabolic demands, removal of metabolic by-products, access for administration of cytoprotective and therapeutic agents, maintenance of endothelial viability and fluid balance. It has been shown, that the requirements for different organs differ substantially. The right solution for MP and preservation is paramount. Up to this date, there is no specific preservation solution for VCAs. As MP is increasingly implemented in solid organ transplantation, and our working group among others showed clear advantage of MP of VCA compared to SCS, it is imperative to generate a preservation solution, tailored to the requirements of VCA. The preservation solution we develop will allow to conduct ex-vivo and pre-clinical studies on the preservation of VCA and potentially other tissues and to further advance the technology. 09/01/2020 Brigham and Women's Hospital B-BIC image of external link icon Therapeutic device Blood Available
Transfemoral Artificial Chordae Implantation System to Repair Mitral Valve Regurgitation Pierre Dupont The proposed technology is intended to treat adult patients with degenerative mitral regurgitation. In mitral regurgitation, the mitral valve fails to close properly. Severe mitral regurgitation leads to heart failure, atrial fibrillation and pulmonary hypertension. While there are about 4 million patients with mitral regurgitation, only those with severe mitral regurgitation are referred for treatment (1.67 million). The standard of care is repair of the valve by open-heart surgery, but only 2% (30,000) opt for surgery owing to its risks and long recovery period. This means that there is a large untapped market for a repair technology that does not involve the risks and trauma of surgery. Catheter-delivered valve repairs provide this alternative solution and the implantation of artificial chordae is a tried-and-true technique in the repair of mitral regurgitation. We have previously developed an instrument for implanting artificial chordae inside the beating heart with the instrument inserted through the apex of the heart. At this time, however, the market has turned away from devices inserted through the apex in favor of devices inserted through the vasculature. The goal of this project is to convert our current instrument into one that can implant artificial chordae from a catheter inserted into the femoral vein in the groin and to demonstrate its capabilities through in vivo swine experiments. Achieving this goal will position us to: (1) recruit a CEO, (2) raise angel and VC funds and (3) engage strategics interested in acquiring the technology. 12/01/2020 Boston Children's Hospital B-BIC image of external link icon Therapeutic device Heart Available
Para-magnetic nanosphere-labelled soluble Dectin-1 as an imaging agent to improve the diagnosis of fungal pneumonias Joshua Fierer The goal of this research is to develop a highly specific, safe, and sensitive method to diagnose fungal pneumonias using enhanced radiological imaging of the lungs. We propose to use solubilized C type lectin receptors (Dectin-1 and/or Dectin-2) that bind specifically to components of the fungal cell wall. C type lectin receptors evolved to recognize carbohydrates that are present on fungi but are absent from host tissues and proteins. As a prototype we chose Dectin-1 (Clec 7a), which recognizes a variety of beta-1, 3-linked and beta-1, 6-linked glucans present on most fungal and plant cell walls. We have demonstrated that both human and mouse Dectin-1 binds to all forms of the dimorphic fungus Coccidioides immitis and to Aspergillus fumigatus hyphae and germinated spores, the tissue invasive forms. Fungal pneumonias are often a lethal complication in immunocompromised hosts. Dimorphic fungi infect normal hosts and in endemic areas of the US dimorphic fungi they cause up to 25% of all pneumonias. We propose to label a soluble Dectin-1/Fc fusion protein with nanospheres that have para-magnetic metallic components that will enhance detection of fungi using MRI or CT imaging and will improve the ability of clinicians to diagnose fungal pneumonias. CT scans and MRI cannot differentiate bacterial pneumonias from invasive fungal pneumonias until the latter are far advanced and more difficult to treat. Early diagnosis should improve outcomes, reduce the unnecessary use of antibiotics, and increase the early use of anti-fungal drugs. MRI and CT are non-invasive imaging technique widely available in medical centers and essentially risk free. The use of an immunologically based imaging agent to add diagnostic specificity to an MRI image is very innovative. 02/01/2017 UCSD UC-CAI image of external link icon Diagnostic device Lung Available
Pro-resolving micro-/nano-particles to improve vascular patency Matthew Spite 09/01/2016 Brigham and Women's Hospital B-BIC image of external link icon Therapeutic device Blood Blood Available
Hyaluronan Enhanced and Biomechanically Designed Trans-catheter Aortic Valve Prosthesis Lakshmi Prasad Dasi While trans-catheter aortic valves (TAVs) bring valve replacement therapy to a larger patient population, the fact that they utilize fixed tissue as leaflets render them less durable and not cost effective from the standpoint of manufacturing, quality control, and storage. There is a strong need for a durable TAV that does not require anti-coagulant therapy to address the age old drawbacks plaguing all artificial heart valves to date. We have developed a potentially disruptive TAV technology that utilizes advanced biomolecule enhanced polymers and biomechanical design principles that has so far demonstrated strength, anti-thrombogenic, and anti-calcific properties. In this project, we will translate our innovative technology towards commercialization through clinical quality device manufacturing, controlled bench studies, and animal trials. 01/12/2017 Ohio State University NCAI-CC image of external link icon Therapeutic device Cardiovascular Available
Screening Diagnostic for COVID-19 using Microfluidic Enrichment and Counting of SARS-CoV-2 Particles Steven Soper The project seeks to repurpose an established technology, which was developed as part of an active NIBIB P41 Biotechnology Resource Center, for diagnosing COVID-19 using a handheld instrument with an assay turn-around time &lt;15 min. The team has demonstrated that their technology can enrich exosomes from the plasma of cancer patients (the size of exosomes is very similar to SARS-CoV-2 virus particles, ~150 nm). They have also developed a nano-Coulter Counter (nCC) that can quantitatively enumerate the number of enriched particles in a label-free manner with 100% detection efficiency and provide near real time results. The envisioned COVID-19 diagnostic product consists of a handheld instrument that accepts a fluidic chip mass-produced using production lines already in-place (same production line used to produce CD, DVDs, and Blu-Ray disks injection molding). The chip enriches viral particles (VPs) using an affinity approach (i.e., aptamers), releases the enriched particles, and counts them using a label-free approach. The handheld instrument, which can be operated at the point-of-care, can be used for thousands of tests with the consumable being the fluidic chip. The assay is also reagent-free. 09/01/2020 University of Kansas MBArC image of external link icon Diagnostic device COVID-19 Available Jaya Gosh
Bill Fay
Electronic probe for high-throughput, low-cost testing of SARS-CoV-2 from breath with accurate results in real-time Jie Huang The team is developing and testing a novel breath analyzer probe that can detect SARS-CoV-2 from exhaled breath in real-time (time to test result less than 30s). The proposed approach is an alternative solution to rRT-PCR for high-throughput SARS-CoV-2 testing. The probe has a limit of detection in the pico-gram range (~ 10,000 virions), and can be specifically designed using antibody chemistry, deployed as an aerosol reactant, to output fingerprint electronic signatures that uniquely indicate SARS-CoV-2. By collecting multiple breaths, the technology can also address the dynamic range, from asymptomatic to late-stage individuals, with sufficient sensitivity and specificity to accurately identify Covid-19 disease. The breath analyzer probe, based on the recently invented Open-Ended Hollow Coaxial Cable Resonator (OE-HCCR) technology, is reliable, user-friendly, portable, and can easily be mass produced at low cost. The breath analyzer probe provides a realistic approach to increase testing for SARS-CoV-2 because it can be rapidly integrated into and adopted by the healthcare system by deploying &gt; 50,000 probes in point-of-care sites (e.g., pharmacies, supermarkets, urgent care centers, etc.). 09/01/2020 MBArC image of external link icon Diagnostic device COVID-19 Available Jaya Gosh
Bill Fay
Clinical Testing of FastDetect Point of Care qPCR System for SARS-CoV-2 Detection Lester Layfield The COVID-19 pandemic has presented many challenges to the health care system. Control of spread of the virus within the community remains a significant challenge requiring adequate healthcare measures including case identification and contact tracing. Seminal to case identification is rapid and accurate testing for the virus. Currently, test results may take several days or longer to receive after taking the sample. Such delays reduce the utility of the results since tested but no reported results may allow patients infected to mingle with the general community further spreading the virus. Testing methods can take several hours or even days, making on-site testing at schools or public events useless as the results are not available when need for entrance or exclusion decisions. The development of a rapid (turnaround time of minutes) testing method would solve many of these issues with rapid triage of people into infected and non-infected groups. The FastDetect instrument represents a device which can rapidly screen individuals for the presence of COVID-19. The test requires approximately 15 minutes to generate results, using conventional qPCR amplification of a single sample with a four-channel fluorescence read-out. The current proposal will test the FastDetect instrument for diagnostic sensitivity and specificity as well as operating characteristics such as throughput and reliability when used by nonlaboratory professionals in a point of care testing environment. 09/01/2020 University of Missouri - Columbia MBArC image of external link icon Diagnostic device COVID-19 Available Jaya Gosh
Bill Fay
Rapid Synthetic Biology-Based Point of Care Assay for SARS-CoV-2 Virus Claudia Gentry-Weeks The proposed solution is a low-cost, paper-based, portable assay that requires no equipment and can detect 50 SARS-CoV-2 virus particles in one hour using only a smartphone for detection and connectivity to a cloud database for analysis. A paper disk will be loaded with assay componentstranscription- translation machinery, a plasmid encoding a gene with a toe-hold switch upstream of a modified, site-specific tobacco etch viral protease (TEVp), a plasmid encoding an inactive luciferase that is activated by TEVp cleavage, and luciferin substrate. Once the paper disk is rehydrated with RNA extracted from the patient specimen (saliva, oral swab, nasal swab fluid), transcription and translation of the genes on the plasmid constructs will occur. Transcription of the toehold switch will result in mRNA that forms a stem-loop structure, blocking translation and TEVp production. Patient saliva or nasal swab specimens will be processed for viral RNA using a rapid, low cost procedure that does not require equipment or commercial kits. Extracted viral RNA from the patient specimen will be added to the paper disk containing the assay components. If SARS-CoV-2 RNA is present, it will bind to the toehold switch upstream of the protease, causing a conformational change in the mRNA, and translation of the TEVp mRNA. TEVp will cleave the inhibitor from the luciferase, resulting in luminescence activity that can be detected and analyzed with a smartphone. All materials and plasmid constructs are available commercially, with the exception of the toehold switches, which can be readily designed and synthesized. 09/23/2020 SPARK image of external link icon Diagnostic assay SARS-CoV-2 Detection Available Claire McDonald
Rick Duke
COVID-19 POC rapid antigen detection CLIA waived device Charles Henry We will develop a rapid, colorimetric point-of-care (POC) antigen test for detection of circulating SARS-CoV-2 nucleocapsid protein in whole blood and nasal swab samples. Current lateral flow assays suffer from low sensitivity and specificity, whereas laboratory ELISAs take significant time from sample-to-answer. Utilizing our patent pending microfluidics technology, we have developed a POC test that combines the simplicity of lateral flow assays with the specificity and sensitivity of ELISA. Our approach is enabled by a revolutionary microfluidic valving system that automatically controls sample manipulation, reagent delivery, and washing with only the addition of sample and the release of a buffer blister pack. Our innovative system uses readily available and inexpensive materials in a layered construction that will be simple and cost-effective to rapidly produce at large scale. Furthermore, the straightforward user experience and absence of specialty equipment to run the test results in an assay that can be used in a wide range of environments. We have developed prototype devices and evaluated their operating characteristics in laboratory settings for both SARS-CoV-2 antibodies and antigens. We are also currently developing a highly specific monoclonal antibody targeting SARS-CoV-2 nucleocapsid protein that will overcome selectivity issues seen with other POC devices. These innovations allow for the adaptation of sensitive and specific ELISA immunoassays in a disposable device that can be used in clinics or at home. Our goal is to rapidly translate our existing technology to clinical testing with banked patient samples while developing partnerships to enable large-scale commercialization. 09/23/2020 SPARK image of external link icon Diagnostic assay SARS-CoV-2 Detection platform Available Claire McDonald
Rick Duke
Development of a Point of Care SARS-CoV-2 ELASA Preston Neff Aptamers, synthetic nucleic acid sequences that bind specific targets, can replace monoclonal antibodies (mAb) and are faster and cheaper to produce. Using aptamers we will develop a cost efficient, point of care detection test for SARS-CoV-2. 09/23/2020 University of Colorado Anschutz SPARK image of external link icon Diagnostic assay Detection of SARS-CoV-2 Available Claire McDonald
Rick Duke
RADX-Tech SPion COVID-19: Mass Spectrometry Platform for Direct SARS-CoV-2 Detection Nathalie Agar As of July, 8th 2020, the WHO reports the global number of COVID-19 cases to be 11,669,259 with total deaths 539,906 and for which the USA accounts for 2,923,432 cases and 129,963 deaths. While a number of states are seeing stabilizing and some decreasing numbers, the country continues to report record high numbers of new cases. Models also indicate the inevitability of a second wave later in the year that could be even more devastating. The needs for COVID-19 testing continue to grow as the country is developing strategies to resume activities in the safest way possible. We here propose to analyze both the spike and nucleocapsid proteins from SARS-CoV-2 from nasopharyngeal (NP) swabs using mass spectrometry and can be readily adapted to analyze other specimens such as saliva, sputum, nasal swab, and oral swab that may carry the virus. The direct analysis of the two proteins with mass spectrometry will provide rapid testing with increased specificity in testing results. The new platform will leverage existing mass spectrometers which are already FDA approved Class I devices, supporting dissemination of the test within the 1-year timeframe. 09/01/2020 Brigham and Women's Hospital, Harvard Medical School B-BIC image of external link icon Diagnostic device COVID-19 Available Erin McKenna
RADX-Tech COVID Smell Test: Augmenting Sensitivity of Testing by Identifying Asymptomatic Pts w Increased Viral Load Mark Albers Self-report of sudden loss of smell increases the odds of being infected with SARS-CoV-2 (10 &acirc; 37-fold). However, self-report of smell function is unreliable. We created a self-administered, &acirc;at home&acirc; 5-minute objective smell test to uncover alterations in smell function and increased risk of infection by SARS-CoV- 2. Our new smell test consists of a physical smell card containing peel and sniff odor labels and a webbased application. The disposable smell card reduces the risk that the smell test serves as a vector of transmission to other patients, research staff, and to health care workers. Each participant accesses the web-based app on their own smartphone, tablet, or computer. In our pilot studies, we validated each participant&acirc;s COVID status by extracting results of clinical SARS-CoV-2 RT PCR assays from electronic health records. We are expanding the smell test from one smell card with three odors to 6 smell cards, each with 3 different odors (18 odors total). Having six different versions of the smell card will afford longitudinal screening several times per week and provide data to construct personalized thresholds for changes in olfactory function. Here we propose to develop the web-based app to conduct longitudinal COVID Smell Test (Aim 1), collect data on asymptomatic health care workers (Aim 2). Effective screening with the COVID smell test will better inform students and employees if they should not report to school or work, and seek an evaluation by a healthcare professional and molecular testing at an early, often asymptomatic, stage of the disease. 09/01/2020 Massachusetts General Hospital B-BIC image of external link icon Diagnostic device COVID-19 Available Erin McKenna
RADX-Tech Microwave Induced Resonance for Assaying Coronavirus by Light Emission Anthony Samir We propose a novel physics-based approach for rapid SARS-CoV-2 detection that (i) has superior sensitivity; (ii) can be performed without specimen contact; (iii) requires no reagents; (iv) can interrogate any sample, (iv) requires no specimen processing; and (vi) has a path to deployment and use by operators without specialized training. The system is based on a trace substance detection approach combining the phenomenon of electromagnetic field induced virus resonant oscillation with ultrasensitive frequency-shifted laser energy detection. Our core innovation is a new approach to low amplitude frequency-shifted laser energy detection. When combined with our deep understanding of the relevant science and the ready availability of necessary components with known supply chains, we have a credible pathway to an affordable, sensitive, rapid, and robust solution to the current massive unmet need for fast, highly sensitive, incommunity and point-of-care SARS-CoV-2 testing. Our technology has specific properties that indicate it will be a highly useful complement to existing RNA and antigen detection technologies. It is expected to: (1) perform as a screening test, which will facilitate more efficient use of scarce reagent-based testing; (2) be widely deployable and usable by personnel without specialized training at the point of care and in non-clinical environments, such as schools, colleges, sporting events, and workplaces; (3) be able to process room and atmospheric air for the detection of circulating viral particles, thereby preventing infections and; (4) provide important information about disinfection adequacy, as it is sensitive to intact viral particles rather than viral RNA or antigens. 09/01/2020 Harvard Medical School, Massachusetts General Hospital B-BIC image of external link icon Diagnostic device COVID-19 Option to license Erin McKenna
RADX-Tech New Handheld Gas Sensors for Airborne SARS-CoV-2 Virus: Rapid COVID-19 Diagnosis from Exhaled Breath Nian Sun We propose to develop handheld gas sensors that will rapidly detect SARS-CoV-2 in exhaled breath in 1~2 seconds with close to 100% sensitivity and specificity based on PI&acirc;s past success on such sensors. The approach is based on electrochemical sensors through molecularly imprinted polymer with part per quintillion (10^-18) sensitivity, fast sensor response and recovery in 1~2 seconds, and ultra-high specificity. Molecular imprinting is a technique in which a thin-layer polymer is formed around the template molecules of interest. The template molecules are then removed after polymerization. As such it leaves an imprint of the exact size and shape of the template molecules in the polymer matrix. This results in a lock (sensor cavity) and key (template molecule) relationship of extremely high specificity. If successful, the proposed handheld SARS-COV-2 sensors will allow rapid low-cost or free point-of-care COVID-19 tests. These handheld SARS-CoV-2 sensors will have a low one-time cost of ~100$ each, which can be used for millions of times of tests in households, schools, businesses, shopping malls, cinemas, etc. We have started the clinical tests with our collaborators at UMass Medical School. We will bring up a prototype SARS-CoV-2 sensor device with a limit of detection of ~1000 copies / mL and ~100% specificity. We expect to get FDA EUA for these SARS-COV-2 sensor systems by December 2020. We expect that these SARS-COV-2 sensor systems will be available to the market by the end of 2020, and save lives. 09/01/2020 Northeastern University B-BIC image of external link icon Diagnostic device COVID-19 Available Erin McKenna
Highly sensitive and specific immunoresistive sensor for point-of-care screening of COVID-19 Jae-Hyun Chung Various rapid screening and detection methods have been developed to rapidly identify SARS-C0V-2 infection for COVID-19 disease management and treatment. Commercially available methods are serological tests and nucleic acid detection by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) assay. Serological tests detect immunoglobulins that specifically recognize SARS-CoV-2 viral proteins using lateral flow immunoassays. This detection scheme is simple, rapid, and low cost. However, the lateral flow assay is limited in sensitivity and specificity. Particularly, the assays cannot detect the target virus in nasal swab samples at an early stage of infection. Due to their limited performance, the lateral flow assays are not recommended as sole diagnostic tools by FDA (1). The qRT-PCR-based assays that detect various regions of SARS-CoV-2 genomic RNA from nasopharyngeal swab and throat swab samples are the gold standard methods currently used for screening patients for COVID-19 positivity. The commercial assays require 6 hours of assay time with expensive equipment. Although the Xpert&Acirc;&reg; Xpress SARS-CoV-2 assay (Cepheid, USA) shows the results in 45 min, the bulky equipment is available only in well-equipped central laboratories with skilled technicians, which is neither suitable for Point-of-Care usage nor for real-time monitoring. Nanomaterials have been investigated as highly sensitive transducers based on electrochemistry (2). Among nanomaterials, single-walled carbon nanotubes (SWCNTs) are one of the potential candidates for enabling a simple resistive transducer for detecting the binding of a target analyte with high sensitivity and specificity. Resistive SWCNT sensors can detect targets by two distinct mechanisms (3-6). One is to change the free carrier density of doped SWCNTs by electrostatic interaction. The other is to change the work function of the metal electrode-SWCNT interface, thus leading to Schottky barrier modulation. When SWCNTs were deposited on gold electrodes on a silicon substrate, both mechanisms play roles in modulating the resistance. Viral particles and bacteria can be detected by monitoring this resistance change (7, 8). The lower limit of detection (LLD) of the swine influenza virus (H1N1) was 177 TCID50 (50% tissue culture infective dose)/mL (7). The LLD for Bacillus subtilis was 100 CFU/mL (8). SWCNTs functionalized with heparin detected dengue virus at concentrations as low as 840 TCID50/mL (9). The LLD was 1 plaque-forming unit (PFU)/mL for detecting H1N1 (10). Also, a similar sensing configuration was applied to detect a peanut allergen protein in food extracts with a detection limit of 5 ng/mL (11). For mRNA detection, the LLD was at attomolar levels, which showed the potential to detect nucleic acid without amplification. In our previous work, nanotips made of SWCNTs could be used for bacterial detection (12). The crossbar junctions coated with SWCNTs were fabricated to detect target bacteria in food samples at a detection limit of 100 CFU/mL (13). However, these assays have been developed based on stiff and bulky substrates, which cannot bend to fit the curves of the human body. Also, the fabrication and integration costs are too high for an inexpensive screening assay. In this proposal, we aim to prototype an immunoresistive sensor that can detect SARS-CoV-2 from nasal swab samples. Our previously developed assay for Mycobacterium tuberculosis (14) will be modified for the highly sensitive and specific detection of SARS-CoV-2 (the causative agent for COVID-19). The portable sensor will consist of a resistive measurement unit with a disposable sensor cartridge. The prototype will be designed and fabricated with ease of operation in mind. The performance of the assay will be equivalent to PCR-based assays but with the time and complexity similar to current lateral flow assays. 09/20/2020 University of Washington WE-REACH image of external link icon Diagnostic device COVID-19 Available Matthew Hartman
Rodney Ho
Harmony Barry Lutz Harmony is a rapid non-laboratory COVID-19 test that detects SARS-CoV-2 RNA from a nasal swab without RNA extraction. It uses isothermal amplification with our own novel polymerase and fluorescence probe design to detect three SARS-CoV-2 RNA regions (green fluorescence) and an internal amplification control (red fluorescence) in the same reaction tube. A test kit includes all consumables needed to test one person &acirc; swab sampler and reaction tube &acirc; in a shelf-stable ready-to-use format. A low-cost base station provides heating, fluorescence detection, and data interpretation (positive, negative, indeterminate). We developed a swab-to-result beta prototype system with dry ready-to-use reaction tubes. It has a limit of detection (LoD) comparable to other EUA tests (2 copy/uL) and no cross-reactivity with SARS and MERS, and we have successfully tested simulated nasal matrix at 5x LoD, RNA extracted from COVID-19-positive clinical nasal swabs, and Accuplex&acirc;&cent; SARS-CoV-2 Reference RNA (1 copy/uL). We have transferred the assay to a commercial partner (InBios) that will produce our DNA polymerase, source reagents (supplier agreements and licenses in progress), and produce test kits. We are working with an engineering design firm (Simplexity) to execute hardware improvements and design for manufacturing, and we have engaged the 3rd largest contract manufacturer in the US (Sanmina). 10/01/2020 University of Washington WE-REACH image of external link icon Diagnostic device COVID Diagnostics Available Matthew Hartman
Rodney Ho
Rapid Diagnostics of SARS-CoV-2/COVID-19 of Asymptomatic People Wishing to Return to Work or School Gajendra Shekhawat "Overview: We propose to develop MEMS based micro cantilever 2D arrays for simultaneous detection of Viral antigen (Nucleocapsid protein (N antigen) and Spike protein (S antigen), IgM and IgG antibodies. Specific Aims: 1. Simultaneous detection of viral antigen, IgG and IgM at once in single testing. 2. To procure specific potential covid-19 antibodies to detect viral antigens (shown in Fig. 4) (i) Nucleocapsid protein (N antigen) (ii) Spike protein (S antigen). 3. In parallel, attempts will be made to screen DNA aptamers against selected viral antigens from designed oligonucleotide library. 4. The specificity and affinity of procured/synthesized bio-receptors will be evaluated using ELISA and other biochemical tests. 5. Immobilization of viral antibodies and anti-viral antibodies onto the integrated micro cantilevers via suitable optimized chemistry for IgG, IgM and antigen testing respectively 6. Testing and validation of assay with real samples (blood/ serum/ swab/breath)" 09/01/2020 Northwestern University NCAI-CC image of external link icon Diagnostic device COVID-19 Available Vara Josyula
Point-of-Care Antigen Detection for SARS-COV-2 from Saliva Hong Qi We are developing lateral flow immunoassay (LFIA) rapid tests for detection of N and S protein of the SARS-COV-2 virus from saliva. LFIA are excellent tools at point-of-care, with results in minutes, with no need of special instrument. The tests are also easy to scale up for production, meeting the need of millions of tests as early as summer of 2020. The key components for antigen detection are antibodies with high specificity and affinity to viral proteins. Qoolabs is using its proprietary QMab&acirc;&cent; method to develop monoclonal rabbit antibodies to N and S Proteins. Monoclonal antibody clones are expected by end of May, 2020. Another key step in viral antigen detection is the disruption of viral particles to expose the antigen so that antibodies could interact with the antigen. By completing previous SBIR contracts from the CDC, Qoolabs has developed a proprietary method to quickly disrupt viral particles and proceed to immunoassays without further cleaning or purification. Combining the highly specific rabbit monoclonal antibodies to N and S protein and the sample treatment method, Qoolabs will quickly generate prototype LFIA tests once the antibodies are available. Prototype tests will be available in mid-June for validation. Large scale production for millions of tests could be initiated as soon as August 2020. 09/01/2020 UC-CAI image of external link icon Diagnostic assay Covid-19 Available Elvira Liclican
BlowFISH: A Non-invasive Collection System for Fast COVID-19 Detection H. Pirouz Kavehpour Our solution is a cheap, non-invasive and massively deployable collection and diagnostic systems for detecting COVID-19 through rapid condensation of exhaled breath. Our platform technology is based on our patented continuous droplet condensation technique which is capable of efficiently extracting particulates and aerosols (virus/bacteria) from humid air or breath. The collection system is agnostic to the detection system used and can be efficiently coupled to existing protocols such as rtPCR meaning that it can be quickly implemented in the field where it can supplement or perhaps displace invasive nasal swabs as the standard for sample detection. Collection of sufficient condensate for testing takes only a handful of breaths and less than a minute. Our technology can easily be modified to become a sentient environmental monitoring system for hospitals, airports or offices spaces. It can also be modified to become a rapid point-of-care diagnostic system. Our point of care diagnostic solution includes an on-chip virus detection using a hydrogel impregnated with ACE2 to capture corona viruses with their capsid intact and tuboFISH to detect the RNA of COVID-19 in the condensed breath. Using turboFISH, which is a high-speed fluorescent in-situ hybridization technique, our point of care diagnostic system will be able to provide results in less than 15 minutes from start to finish with an extremely small limit of detection while processing more than 100 samples per hour at each of our detection systems implemented in the field. 09/01/2020 UCLA UC-CAI image of external link icon Diagnostic assay Covid-19 Available Elvira Liclican
Saliva COVID-19 Infection &amp; Immunity Test (SCOVID-19 II Test) David Wong Concurrent detection of presence of SARS-CoV-2 infection (viral RNA from isolated virus) and of host immunity (IgG, IgM and IgA antibodies): saliva sample, allows remote sampling, thereby removing exposure of health care workers, direct detection with no sample processing, allowing high throughput robotics, TAT 1.5 hr. Platform is peer-reviewed, NIH funded, and CLIA-qualified. 09/01/2020 UCLA UC-CAI image of external link icon Diagnostic assay Covid-19 Available Elvira Liclican
A Versatile Point-of-Care Platform for Real-Time Label-Free Multianalyte COVID-19 Diagnosis Moshiur Anwar Immediate and widely accessible diagnostics is the key factor needed for all patients at risk for contracting the rapidly spreading, and potentially fatal pathogen, COVID-19. Accurate, on demand, testing demands a versatile, sensitive and scalable platform capable of incorporating both protein (antigen) and RNA-based biodetection strategies, heretofore confined to a laboratory setting, in a point-of-care setting. Here we introduce a platform deeply integrating microfluidics, silicon nanophotonics and integrated circuits (&acirc;computer chip&acirc; technology) to achieve both viral RNA and antigen detection on a single, low-cost, disposable platform. Our sensors are uniquely sensitive and massively reduce assay complexity through label free detection of viral RNA and antigen using using multiplexed banks of functionalized on-chip nano-photonic ring resonators integrated with electronics to achieve near single molecule sensitivity. This obviates the labor intensive process of introducing secondary antibodies for protein diagnostics and RNA amplification for PCR. A high scalable architecture enables a large panel of measurements on a single die. Synergistic design of on-chip microfluidics enables multiple, independent chemical environments on-chip, simultaneously measurement of proteins, small molecules and RNA on a single platform. Our solution leverages the economies of scale of the computer chip industry to rapidly scale our design at costs compatible with disposable devices. Through RADx our team spanning physicians and experts in biosensor design at the UC San Francisco and experts in microelectronic and photonic sensors at UC Berkeley, will build on our demonstrated silicon-photonic label-free biosensing platform to create a disposble diagnostic platform for COVID-19. 09/01/2020 UCSF UC-CAI image of external link icon Diagnostic assay Covid-19 Available Elvira Liclican
A high-throughput respiratory viral antigen profiling platform for COVID-19 surveillance Weian Zhao We seek to develop a robust, highly scalable respiratory viral panel analysis platform that can be deployed immediately for highly-sensitive detection of viral antigens using an antibody microarray on the scale of &gt;20,000 samples per day. These microarrays can probe hundreds of different epitopes from 20+ common respiratory viruses including SARS-CoV-2, SARS-1, MERS, the 4 seasonal human coronavirus strains, along with adenovirus, RSV, MPV, parainfluenza and Influenza viruses in a single test. As we will likely have the flu epidemic and the coronavirus epidemic at the same time in a more devastating next winter, our ability to analyze the complete respiratory virus panel is therefore critical and advantageous compared to existing methods (e.g. RT-PCR, lateral flow) that typically only detect one or two targets in fully discriminating these viral infections and identifying the cause of infection when they share similar symptoms. Our platform comprises: a) Respiratory Antibody Microarray, based on our experience developing similar tests for flu viruses and our recent Coronavirus serological profiling test against 65 antigens from 23 viruses known to cause respiratory tract infections, including SARS-CoV-2 (R. de Assis et al., bioRxiv, 2020, doi:10.1101/2020.04.15.043364). b) A modular, scalable and robust microarray imaging system that will be integrated with existing sample (nasal swab specimen) collection and processing used in established RT-PCR assay. c) Software with algorithms for automated data collection and cloud-based analysis to inform public health policies for containment and mitigation measures. 09/01/2020 UC Irvine UC-CAI image of external link icon Diagnostic assay Covid-19 Available Elvira Liclican
Portable wireless electronic SARs CoV-2 aptamer/antibody and antigen biosensor for global health Ratneshwar Lal The proposed work aims for developing a handheld, universal platform with capability of label-free detection of SARs-CoV-2 virus, protein, antibody, and genetic markers thereof. Our point of care (POC) platform either screens or tests for multiple/individual viruses and/or the antibodies which are raised against them. The existing device, at UCSD, would need to be integrated with a microfluidics module and studied for scalability to arrays of sensors and related instrumentation platforms. We estimate viral detection with &gt;98% specificity and 20-30 virus particle sensitivity in &lt; 1 hour. With integration of sensors for virus, protein and antibody, our platform would be indispensable, serving as a general pathology laboratory for a wide range of applications including diagnosis of viral diseases, protein and antibody screening to predict disease risk, treatment response and monitoring vaccine development 09/01/2020 UCSD UC-CAI image of external link icon Diagnostic assay Covid-19 Available Elvira Liclican
Quantitative Point-of-Care SARS-CoV-2 Diagnostic Assay Gordon Murtaugh The University of California San Francisco (UCSF) has developed an inexpensive quantitative point-of-care (POC) test for the SARS-CoV-2 virus. UCSF&acirc;s 15-minute assay delivers quantitative information about a patient&acirc;s COVID viral load, which provides critical information to clinicians and patients about the state of a patient&acirc;s COVID infection. In contract, other POC tests return only qualitative (e.g., yes/no) results. The assay is based on detection of the &acirc;E&acirc; (envelope) and &acirc;N&acirc; (nucleoprotein) genes of SARS-CoV-2. The assay uses isotheral amplification methods, which provide advantages over current standard RT-PCR methods, such as rapid turnaround and elimination of the need for a thermal cycler. The assay is performed using UCSF&acirc;s droplet-based ddPCR technology platform, which compartmentalizes nucleic acid amplification reactions into pico-liter droplets that act as individual micro-reaction tubes, preventing inter-sample intervention and increasing tolerance to inhibitory substances from the sample which often contaminate standard RT-PCR tests, leading to false negative results. The assay is sensitive, quantitative, specific, and reproducible. The product is simply designed, so that it can be used by nearly anyone, including those without professional training. The diagnostic has potential for home use. 09/01/2020 UCSF UC-CAI image of external link icon Diagnostic assay Covid-19 Available Elvira Liclican