U01NS132345

Soluble Epoxyde Hydrolase Inhibitor GSK2256294 for Acute Ischemic Stroke - Project Summary

The proposed translational studies will determine the cereroprotective efficacy of GSK2256294, an FDA-approved soluble Epoxyde Hydrolase (SEH) inhibitor. Inhibition of SEH increases the endogenous levels of its substrate Epoxyeicosatrienoates (EETs), which are endogenous brain lipid mediators with multiple mechanisms of action that are beneficial in stroke, including vasodilation, cytoprotection, anti-inflammation, and suppression of platelet aggregation.

Ample evidence from our group and others demonstrate that SEH inhibition and gene deletion reduce infarct size and improve functional outcomes after experimental ischemia-reperfusion injury in brain. The benefits of SEH inactivation in experimental ischemic stroke have been demonstrated in young and old male and female mice with diabetes and hypertension.

Importantly, gain of function mutations in the SEH gene, called EPHX2, are associated with increased risk of ischemic stroke and worse outcome in humans, whereas carriers of a loss-of-function mutation have reduced risk of stroke and improved outcome.

We have recently completed a Phase IB clinical trial using GSK2256294 in patients with aneurysmal subarachnoid hemorrhage (SAH). The trial demonstrated that GSK2256294, administered orally for 10 days, is safe and well tolerated in critically ill patients with SAH. Although not powered for efficacy, the trial also showed trends for improvement in relevant functional outcomes.

The proposed studies will test the efficacy of GSK2256294 in the NINDS Stroke Preclinical Assessment Network (SPAN) using the Transient MCAO Occlusion (TMCAO) model in young adult and aged mice with type 2 diabetes. PI will participate on the SPAN Steering Committee, attend all SPAN meetings, and work collaboratively with all awarded sites, the Coordinating Center (CC), and NINDS program staff to achieve the goals of the SPAN program.

GSK2256294 will be synthesized by a highly experienced contract research organization (BOC Sciences) and will be provided in a sufficient amount to be tested in parallel by the entire SPAN network. PI will work with the CC to validate activity, concentration, and solubility of GSK2256294 and test its efficacy in the TMCAO model in a randomized and blinded fashion.

The long-term goal is to support the use of GSK2256294 in a clinical trial for acute ischemic stroke (AIS) and advance its use in AIS patients. Because GSK2256294 is already approved by the FDA and has an established safety record in humans, including in hemorrhagic stroke patients, it can be advanced rapidly for testing in clinical trials of AIS if efficacy is confirmed through rigorous testing by the SPAN network.

Oregon Health & Science University

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Portland, Oregon 972393011 United States

Single Zip Code

Stroke Preclinical Assessment Network (SPAN) to Support Translational Studies For Acute Cerebroprotection- Interventions (U01 Clinical Trial Not Allowed) (RFA-NS-22-066)

Amendment Since initial award the total obligations have increased 44% from $693,000 to $994,455.