Project Grant R44NS134446

GENE THERAPY FOR IDIOPATHIC PARKINSON'S DISEASE: IN VIVO VALIDATION - IDIOPATHIC PARKINSON'S DISEASE (IDPD) AFFECTS OVER 1% OF AGING POPULATION, WITH NO CURRENT CURE OR DISEASE- MODIFYING THERAPY AVAILABLE FOR THIS DEVASTATING NEURODEGENERATIVE DISEASE. UNLIKE GENETIC FORMS OF PARKINSON'S, IDPD PATIENTS, WHO CONSTITUTE APPROXIMATELY 80% OF ALL PARKINSON'S CASES, HAVE NO FAMILY HISTORY OR GENETIC MUTATIONS THAT CAN EXPLAIN THIS DISEASE. MARK THERAPEUTICS (MARKTX) ADDRESSES THE UNMET NEED OF IDPD PATIENTS BY DEVELOPING A FIRST-IN-CLASS DISEASE-MODIFYING GENE THERAPY THAT UTILIZES ADENO-ASSOCIATED VIRAL (AAV) GENE THERAPY TAILORED TO SPECIFIC CELLULAR DEFICIT FOUND IN IDPD PATIENTS. THIS THERAPY COMPENSATES FOR PATHOGENIC LOSS OF A PLA2G6L PROTEIN, RESTORES CRITICAL CELLULAR FUNCTIONS, AND HALTS THE PATHOLOGICAL LOSS OF DOPAMINERGIC (DA) NEURONS IN BRAIN REGIONS RESPONSIBLE FOR MOTOR DISFUNCTION. FOLLOWING SUCCESSFUL COMPLETION OF OUR PHASE I PROJECT, WE NOW PROPOSE AN SBIR PHASE II PROGRAM TO OPTIMIZE AND VALIDATE THE THERAPEUTIC EFFICACY AND SAFETY OF MARK202 (THE LEAD CANDIDATE FOR MARKTX GENE THERAPY) IN ADVANCED ANIMAL MODELS (INCLUDING NHP) THAT RECAPITULATE CRITICAL HALLMARKS OF IDPD IN AGING PATIENTS. AIM 1: OPTIMIZE AND VALIDATE IDPD-LIKE MOUSE MODELS THAT BEST REPRESENT PROGRESSIVE AGE-DEPENDENT PATHOLOGY SEEN IN IDPD PATIENTS. WE WILL COMPARE SEVERAL MOUSE MODELS, AND FOCUS ON VALIDATION OF IDPD-LIKE PHENOTYPE IN MARKTX'S PFF-ENHANCED HYBRID MODEL AIM 2: VALIDATE THE EFFICACY AND SAFETY OF OUR LEAD THERAPEUTIC CANDIDATE (MARK202) IN IDPD-LIKE AGING AND PFF- ENHANCED HYBRID MOUSE MODELS AT EARLY AND LATER STAGE OF DISEASE PROGRESSION. WE WILL PARTICULARLY FOCUS ON MARK202'S ABILITY TO: (A) STOP PATHOLOGICAL LOSS OF DA NEURONS IN SNC, (B) SLOW PROGRESSION OF MOTOR DYSFUNCTION, AND (C) DEMONSTRATE THERAPEUTIC EFFICACY AGAINST OTHER PATHOLOGICAL HALLMARKS OF IDPD HUMANS. AIM 3: CONDUCT PRECLINICAL TESTING OF MARKTX THERAPY IN NON-HUMAN PRIMATE (NHP) MODEL OF PD. THE MARKTX TEAM BRINGS STRONG SCIENTIFIC BACKGROUND AND BUSINESS EXPERIENCE, MAKING US FULLY QUALIFIED TO SUCCESSFULLY ACHIEVE ALL THE GOALS OF PHASE II PROPOSAL. REACHING WELL-DEFINED MILESTONES WILL FURTHER DE-RISK MARK'S THERAPY AND VALIDATE THE DISEASE-MODIFYING POTENTIAL OF OUR LEAD CANDIDATE IN IDPD-LIKE ANIMAL MODELS. NINDS/SBIR PHASE II FUNDING IS ESSENTIAL FOR COMPLETING PRECLINICAL STUDIES AND COMMERCIALIZING OUR PROMISING, FIRST-IN-CLASS DISEASE-MODIFYING GENE THERAPY DESIGNED FOR IDPD PATIENTS. WE BELIEVE OUR INNOVATIVE THERAPEUTIC APPROACH WILL BE A GAME-CHANGER AND A MAJOR STEP TOWARDS ULTIMATE VICTORY IN THE FIGHT AGAINST THIS DEVASTATING, CURRENTLY INCURABLE DISEASE AFFECTING THE AGING POPULATION. THE GOALS OF MARKTX'S PROPOSAL FULLY ALIGN WITH THE MISSION OF NINDS.