Friday, 06/05/2020

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 protein’s 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 protein’s 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 CTBp’s 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 CTBp’s 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 CTBp’s 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."" 01/01/1900 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 patient’s 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 doctor’s office or at home for over 15 million patients worldwide who routinely receive oral anticoagulants to prevent venous and arterial thrombosis, the world’s 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 OTEG’s 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. 01/01/1900 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 team’s 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. 01/01/1900 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 Children’s 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 patient’s 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 Development of 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. 08/01/2017 Case Western Reserve University NCAI-CC image of external link icon 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 Alzheimer’s 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. 01/01/1900 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. 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."" 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. 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."" 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 patient’s 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
Test McTest Great technology that cures things 04/20/2020 University of Florida UF Biologic Gator orange and blue