Project Grant R42HL160429

LIPID RECEPTOR GPR31 AS A TARGET FOR ANTI-THROMBOTIC AND STROKE THERAPY - DESPITE PREVALENT USE OF ANTI-PLATELET AND ANTI-LIPID THERAPIES, STROKE REMAINS THE THIRD MAJOR CAUSE OF DEATH AND IS THE LEADING CAUSE OF ADULT DISABILITY IN THE US WITH AN ESTIMATED COST IN THE RANGE OF $34 BILLION ANNUALLY. APPROXIMATELY 20% OF THE ANNUAL 795,000 STROKE PATIENTS DIE WITHIN ONE YEAR AND 15-30% ARE PERMANENTLY DISABLED. ANTIPLATELET THERAPY IS MAINLY USED FOR PRIMARY PREVENTION OF ACUTE ISCHEMIC STROKE IN CEREBROVASCULAR DISEASE. BIOACTIVE FATTY ACIDS ARE A NEW CLASS OF MOLECULAR TARGETS THAT HOLD GREAT THERAPEUTIC POTENTIAL BECAUSE OF THEIR DIVERSE ROLE AS SIGNALING MOLECULES THAT REGULATE METABOLISM AND INFLAMMATION. THE OXIDATION OF ARACHIDONIC ACID BY 12-LOX RESULTS IN THE PRODUCTION OF A NUMBER OF BIOACTIVE LIPIDS INCLUDING THE METABOLITE 12(S)-HETE. THE LIPID RECEPTOR GPR31, AN ORPHAN CLASS A GPCR, IS A 12(S)- HETE RECEPTOR RECENTLY SHOWN TO BE INVOLVED IN INFLAMMATORY SIGNALING. WE RECENTLY DISCOVERED THAT GPR31 MEDIATES 12(S)-HETE PROTHROMBOTIC SIGNALING IN PLATELETS AND PROMOTES GLUTAMATE-INDUCED OXIDATIVE TOXICITY IN NEURONAL CELLS. THEREFORE, WE PROPOSE THAT TARGETING GPR31 MAY PROVIDE A THERAPEUTIC PATH TOWARDS DEVELOPMENT OF A SAFE AND EFFECTIVE ANTIPLATELET THERAPY THAT IS COUPLED WITH SECONDARY NEUROPROTECTIVE EFFECTS FOR MITIGATING AGAINST THE ACUTE NEUROLOGIC SEQUELA OF STROKE TO PROVIDE A MORE EFFECTIVE AND SAFER ALTERNATIVE OPTION OR ADJUNCT TO FIBRINOLYTIC THERAPY. WE HAVE RECENTLY SUCCEEDED IN IDENTIFYING THE FIRST EFFECTIVE GPR31 ANTAGONIST USING OUR CELL-PENETRATING, MEMBRANE-TETHERED, PEPDUCIN TECHNOLOGY TO BE VALIDATED IN THESE PRECLINICAL IND-ENABLING STUDIES AS AN ANTI-PLATELET AND ANTI-STROKE AGENT. WE SHOW HERE THAT THIS I3-LOOP DERIVED GPR31 LIPOPEPTIDE HAS POTENT ANTIPLATELET ACTIVITY AND NEARLY COMPLETELY SUPPRESSES ARTERIAL THROMBOSIS WITHOUT AN EFFECT ON HEMOSTASIS IN MICE. PRELIMINARY DATA WITH THE GPR310 PEPDUCIN SHOWS A HIGHLY SIGNIFICANT REDUCTION IN STROKE INFARCT AREA IN MICE SIMILAR TO THE PROTECTIVE EFFECT OF GPR31-DEFICIENCY. FURTHERMORE, WE PROVIDE EVIDENCE FOR A DIRECT NEUROPROTECTIVE EFFECT OF THE GPR310 PEPDUCIN ON HT22 NEURONAL CELLS SUBJECTED TO GLUTAMATE MEDIATED OXIDATIVE STRESS. THE GOAL OF THIS PHASE 2 STTR PROJECT IS TO DEVELOP THE GPR310 PEPDUCIN AS A COLLABORATIVE EFFORT BETWEEN OASIS PHARMACEUTICALS (LEXINGTON, MA), TUFTS MEDICAL CENTER (BOSTON, MA) THAT WOULD PROVIDE A ROBUST IND DATA PACKAGE REQUIRED TO ADVANCE THE INITIAL COMMERCIAL DEVELOPMENT OF THE FIRST GPR31 INHIBITOR AS A DUAL ANTIPLATELET, ANTI-STROKE DRUG. THIS DRUG DEVELOPMENT PROGRAM WOULD ESTABLISH THE SCIENTIFIC MERIT OF THE GPR31 TARGET BY ACCOMPLISHING THE MAJOR MILESTONES AT THE END OF 2 YEARS OF GLP SAFETY/PHARMACOLOGY AND EFFICACY IN STROKE MODELS THROMBOLYTIC THERAPY TO SUPPORT A PHASE I FIRST-IN-HUMAN CLINICAL TRIAL.