Project Grant R43HL164233

TARGETING GPR146 FOR THE TREATMENT OF HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA - PROJECT SUMMARY VESICLE THERAPEUTICS INC AIMS TO DEVELOP AND COMMERCIALIZE A NEW THERAPY FOR HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HOFH). A MAJORITY OF HOFH IS CAUSED BY MUTATIONS IN BOTH ALLELES OF THE GENE ENCODING THE LDL RECEPTOR (LDLR). SINCE THE EFFICACY OF BOTH STATINS AND PCSK9 ANTIBODY THERAPIES LARGELY DEPENDS ON FUNCTIONAL LDL RECEPTORS, PATIENTS WITH HOFH SHOW LIMITED RESPONSES TO THESE EXISTING THERAPIES. OTHER THAN RECENTLY APPROVED EVINACUMAB, AN ANTIBODY THERAPY AGAINST ANGIOPOIETIN-LIKE 3 (ANGPTL3), FEW OPTIONS ARE AVAILABLE TO TREAT THIS DISEASE. THERE IS STILL AN UNMET MEDICAL NEED FOR DEVELOPING NEW TARGETED THERAPIES TO LOWER BOTH LDL-C AND LIPIDS IN HOFH. GRP146 HAS RECENTLY EMERGED AS AN EXCITING AND POTENTIAL NEW THERAPEUTIC TARGET FOR HOFH. OUR GOAL IS TO LEVERAGE OUR PROPRIETARY DELIVERY TECHNOLOGY TO DEVELOP A NEW GPR146 THERAPY FOR HOFH. THE OVERALL OBJECTIVE OF THIS PHASE I SBIR PROJECT IS TO DEMONSTRATE THAT SILENCING OF GPR146 BY PROPRIETARY GECTOSOME DELIVERY OF LWACAS13A/GPR146 CRRNA IS EFFICACIOUS IN LOWERING BOTH LDL-C AND LIPIDS WITH ACCEPTABLE SAFETY PROFILE IN MICE, ENABLING A NEW THERAPY FOR HOFH.