Project Grant R42EY031625

PREVENTION OF CORNEAL TRANSPLANT REJECTION USING AAV-BDRK-401 THERAPY - PROJECT DESCRIPTION CORNEAL BLINDNESS IS ONE OF THE LEADING CAUSES OF VISION LOSS WORLDWIDE, WITH 10 MILLION INDIVIDUALS HAVING BILATERAL CORNEAL BLINDNESS GLOBALLY. ALLOGENEIC CORNEAL TRANSPLANTATION (CT) TO TREAT GENETIC AND ACQUIRED CORNEAL BLINDNESS IS THE MOST COMMON FORM OF TISSUE TRANSPLANTATION WORLDWIDE, ANNUALLY ACCOUNTING FOR >50,000 SURGERIES IN THE UNITED STATES AND ~180,000 GLOBALLY. IN HIGH-RISK CT, WHICH ACCOUNTS FOR >20% OF THE 180,000 TRANSPLANTS PERFORMED WORLDWIDE ANNUALLY, ALL GRAFTS ARE REJECTED WITHIN 10 YEARS OF CT, DESPITE THE CURRENT STANDARD OF CARE, TOPICAL AND SYSTEMIC IMMUNOSUPPRESSIVE AGENTS WHICH HAVE DOSE-LIMITING ADVERSE SIDE-EFFECTS INCLUDING VISION LOSS. BEDROCK THERAPEUTICS' GOAL IS THE CLINICAL TRANSLATION OF OUR SINGLE DOSE EX VIVO ADENO-ASSOCIATED VIRUS (AAV) GENE THERAPY APPROACH OF THE CORNEAL DONOR TISSUE TO SHIELD IT FROM THE HOST'S IMMUNE RESPONSE. PHASE I STTR MILESTONES WERE SUCCESSFULLY ACHIEVED; A NOVEL LEAD CANDIDATE (BDRK-401) THAT DEMONSTRATES IMMUNOSUPPRESSION AND ANTI-VASCULARIZATION FUNCTIONS WAS SELECTED AND A PROTOCOL FOR EFFICIENT CORNEAL GRAFT GENE TRANSFER WAS OPTIMIZED TOWARDS FEASIBILITY OF APPLICATION IN A HOSPITAL SETTING. FURTHERMORE, CORNEAL GRAFTS TREATED WITH AAV-BDRK-401 PRIOR TO HIGH-RISK CT WERE COMPLETELY PROTECTED FROM ACUTE IMMUNOLOGICAL REJECTION IN A RABBIT MODEL. THE OBJECTIVE OF THIS PHASE II PROPOSAL IS TO ADVANCE THE CLINICAL DEVELOPMENT OF BDRK-401 FOR PREVENTION OF CT REJECTION IN HUMANS BY RECEIVING FDA GUIDANCE, LARGE SCALE AAV-BDRK-401 MANUFACTURING, AND BY PERFORMING A LONG-TERM SAFETY AND EFFICACY STUDY. SUCCESSFUL COMPLETION OF THESE GOALS WILL GENERATE A BDRK-401 DATA PORTFOLIO SUFFICIENT FOR IND APPLICATION SUBMISSION AND, OPTIMISTICALLY, ATTRACT SIGNIFICANT INVESTMENT FOR GMP AAV-BDRK-401 PRODUCTION AND THE EXECUTION OF A PHASE I/II CLINICAL TRIAL. WHILE BEDROCK'S INITIAL FOCUS IS ON PREVENTING HIGH-RISK CORNEAL TRANSPLANT REJECTION, OUR NOVEL IMMUNOMODULATORY TECHNOLOGY IS A SINGLE DRUG ALSO APPLICABLE TO OTHER OCULAR AND NON-OCULAR DISEASES INCLUDING THE PREVENTION OF REJECTION IN ANY SOLID ORGAN TRANSPLANTATION, WET AGE-RELATED MACULAR DEGENERATION, AND TYPE 1 DIABETES.