Project Grant R41EY033262

IMMUNOSUPPRESSIVE GENE THERAPY FOR OCULAR GRAFT VS HOST DISEASE - ABSTRACT BEDROCK THERAPEUTICS, INC., IS DEVELOPING A METHOD OF CONTROLLING THE IMMUNOLOGIC RESPONSE TO ALLOGENIC HEMATOPOIETIC STEM CELL TRANSPLANTS (HSCT) WITH THE AIM OF PREVENTING OCULAR MANIFESTATIONS OF GRAFT VS HOST DISEASE (OGVHD), WHICH SIGNIFICANTLY LOWER THE QUALITY OF LIFE OF AFFLICTED PATIENTS. OVER 20,000 PATIENTS RECEIVE ALLOGENIC HSCTS PER YEAR IN THE US TO TREAT HEMATOLOGICAL DISORDERS. OF THESE, AN ESTIMATED 35-54%, OR APPROXIMATELY 7,000-11,000 PATIENTS ANNUALLY, DEVELOP OGVHD. OGVHD IS A MANIFESTATION OF CHRONIC GRAFT VS HOST DISEASE. THE MOST COMMON CLINICAL DEVELOPMENT OF OGVHD IS DRY EYE, OR KERATOCONJUNCTIVITIS SICCA, WHICH LEADS TO SYMPTOMS SUCH AS OCULAR IRRITATION, PAIN, CONJUNCTIVAL REDNESS, PHOTOPHOBIA, AND REDUCED VISUAL ACUITY. THE DRY EYE OF OGVHD SIGNIFICANTLY REDUCES QUALITY OF LIFE OF HSCT PATIENTS AND LIMITS THEIR DAILY ACTIVITIES. THERAPIES FOR OGVHD ARE LARGELY INEFFECTIVE (RESPONSE RATE OF ONLY 23% AT 6 MONTHS) AND ARE DIRECTED AT REDUCING SYMPTOMS, CONTROL OF CHRONIC DISEASE, AND PREVENTION OF TISSUE DAMAGE. TREATMENTS INCLUDE THE USE OF MULTIPLE DAILY APPLICATIONS OF TOPICAL LUBRICANTS, CALCINEURIN INHIBITORS, CORTICOSTEROIDS, AUTOLOGOUS SERUM, IN ADDITION TO THE USE OF BANDAGE CONTACT LENSES, LIMBAL OR AMNION MEMBRANE TRANSPLANTATION, AND/OR SYSTEMIC IMMUNOSUPPRESSANTS. DESPITE THESE TREATMENTS THE THERAPEUTIC RESPONSE IS POOR RESULTING IN SIGNIFICANTLY REDUCED VISUAL FUNCTION AND THUS A LARGE UNMET NEED FOR EFFECTIVE TREATMENT OF OGVHD. GIVEN THE CONSIDERABLE NUMBER OF HSCT PERFORMED ANNUALLY IN THE US AND THE HIGH INCIDENCE OF OGVHD THERE IS A CRITICAL NEED FOR AN EFFECTIVE AND PRACTICAL MEANS OF TREATMENT OF OGVHD. BEDROCK THERAPEUTICS' STRATEGY FOR TREATMENT OF OGVHD IS BASED ON THE IMMUNOMODULATORY ACTIVITIES OF HUMAN LEUKOCYTE ANTIGEN G (HLA-G) PROTEINS, WHICH ARE NATURAL PROTEINS THAT ACT TO PREVENT MATERNAL REJECTION OF THE DEVELOPING FETUS. OUR INNOVATIVE OPTIMIZED GENE THERAPY METHODOLOGY RELIES ON USE OF ADENO-ASSOCIATED VIRUS (AAV) TO DELIVER A NOVEL ENGINEERED, HLA-G BASED, SINGLE CHAIN IMMUNOMODULATORY (SCIM) PROTEIN TO MODULATE THE IMMUNOLOGIC RESPONSE FOLLOWING HSCT. TO DEVELOP A SINGLE DRUG TO EASE REGULATORY DEVELOPMENT, BEDROCK HAS ENGINEERED A FUNCTIONAL SCIM PROTEIN (BDRK#004) WHOSE CONFORMATION MIMICS A BETA2-MICROGLUBULIN (B2M) BOUND HLA-G DIMER COMPLEX WHOSE CDNA CAN BE PACKAGED AND DELIVERED USING A SINGLE AAV8 VECTOR PACKAGED WITH A SELF-COMPLEMENTARY GENOME, WHICH ARE ENHANCED >10-FOLD IN TRANSDUCTION EFFICIENCY COMPARED TO SINGLE-STRAND AAV GENOMES. THIS INNOVATIVE THERAPEUTIC WILL FULFILL THE UNMET NEED FOR A SAFE AND EFFECTIVE SINGLE DOSE DRUG FOR OGVHD AND POSSIBLY OTHER IMMUNE-MEDIATED OCULAR DISEASES, SUCH AS KERATITIS, DIABETIC RETINOPATHY, AND AGE-RELATED MACULAR DEGENERATION. BEDROCK THERAPEUTICS PROPOSES IN THIS PHASE I APPLICATION TO EVALUATE ITS SINGLE DOSE SCIM DRUG FORMULATION FOR TOLERABILITY AND FUNCTION ON PRIMARY HUMAN T CELLS (AIM 1) AND ITS EFFICACY, SAFETY, AND BIODISTRIBUTION IN OUR MURINE MODEL OF OGVHD (AIM 2).