Project Grant R43NS127620

KV2.1-TARGETED FIRST IN CLASS NEUROPROTECTIVE THERAPEUTIC FOR ACUTE ISCHEMIC STROKE - PROJECT SUMMARY ACUTE ISCHEMIC STROKE (AIS) IMPACTS 795,000 AMERICANS PER YEAR, LEAVING 90% OF PATIENTS WITH CHRONIC DISABILITY. PREVALENT CASES OF AIS IN THE US WERE ESTIMATED AT 6.7M IN 2017, TRANSLATING TO 6M AMERICANS LIVING WITH PERMANENT STROKE-RELATED DISABILITY. AIS IS CHARACTERIZED BY CEREBROVASCULAR BLOCKAGE THAT RESULTS IN THE FORMATION OF A CENTRAL INFARCT WITH A SURROUNDING ISCHEMIC PENUMBRA; THE GOAL FOR NEUROPROTECTION IS BASED ON THE FUNDAMENTAL CONCEPT OF PENUMBRAL PRESERVATION (A.K.A. PENUMBRAL FREEZING). CURRENTLY, THE ONLY APPROVED THERAPY FOR PATIENTS SUFFERING FROM AIS IS THE THROMBOLYTIC AGENT ALTEPLASE (TPA), APPROVED IN 1996 AND BURDENED BY EXPANSIVE SIDE EFFECTS, A HOST OF CONTRAINDICATIONS RESTRICTING ELIGIBLE PATIENT POPULATIONS, AND A LIMITED THERAPEUTIC TIME WINDOW. IMPORTANTLY, THE USE OF MECHANICAL THROMBECTOMY HAS DRASTICALLY INCREASED IN THE PAST DECADE, BRINGING ALONG IMPROVED CLINICAL OUTCOMES. IT HAS BEEN STRONGLY ARGUED THAT THROMBECTOMY OUTCOMES CAN BE FURTHER IMPROVED BY NEUROPROTECTIVE THERAPIES THAT SALVAGE NEURONAL LOSS IN THE PENUMBRA. OUR TEAM HAS IDENTIFIED A SIGNALING PATHWAY THAT IS UBIQUITOUSLY ACTIVATED FOLLOWING ISCHEMIC INJURY, ENABLING THE COMPLETION OF NEURONAL PROGRAMMED CELL DEATH. OUR LEAD NEUROPROTECTIVE, CM-EA1, SPECIFICALLY DISRUPTS THIS NEURONAL CELL DEATH PATHWAY. CM-EA1 IS BEING DEVELOPED TO TREAT PATIENTS SUFFERING FROM AIS, TO PREVENT NEURONAL LOSS IN THE ISCHEMIC PENUMBRA, TRANSLATING TO DECREASED DISABILITY-ADJUSTED LIFE YEARS (DALYS) FOR PATIENT SUFFERING FROM AIS. IN THIS APPLICATION, WE WILL DEMONSTRATE EFFICACY VIA A RIGOROUS RAT TRANSIENT MIDDLE CEREBRAL ARTERY OCCLUSION (TMCAO) DOSE-ESCALATION STUDY. FOLLOWING THESE KEY EFFICACY STUDIES, WE WILL ADVANCE CM-EA1 TO AGED RODENT MODELS AND LARGE GYRENCEPHALIC ANIMALS IN A PHASE II DEVELOPMENT PROGRAM. OUR MULTIDISCIPLINARY TEAM BRINGS TOGETHER A UNIQUE COMBINATION OF ACADEMIC, CLINICAL AND COMMERCIAL EXPERTISE THAT WILL PERMIT THE DEVELOPMENT OF A LIFE-CHANGING DRUG FOR AIS PATIENTS.