Project Grant R41HL162212

DEVELOPMENT OF A GECTOSOME THERAPY FOR CARDIOVASCULAR DISEASES - 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. THERE IS NO CURE FOR HOFH, AND FEW OPTIONS ARE AVAILABLE TO TREAT THE DISEASES. ANGIOPOIETIN-LIKE 3 (ANGPTL3) HAS EMERGED AS A POSSIBLE THERAPEUTIC TARGET FOR HOFH AS INDIVIDUALS DEFICIENT IN ANGPTL3 DO NOT DEVELOP CORONARY ATHEROSCLEROTIC PLAQUE. THE RNA TARGETING CRISPR ENZYME LWACAS13 CAN TURN OFF GENES BY RNA DEPLETION ANALOGOUS TO RNAI BUT WITH VERY LOWER RATE OF OFF-TARGET GENE SILENCING. THE ABSENCE OF SAFE DELIVERY METHODS CURRENTLY LIMITS THE THERAPEUTIC POTENTIAL OF LWACAS13. THE LIU LABORATORY AT THE UNIVERSITY OF COLORADO-BOULDER DEVELOPED AN INNOVATIVE INTRACELLULAR BIOLOGICS DELIVERY SYSTEM CALLED GECTOSOMES. THE OVERALL OBJECTIVE OF THIS PHASE I STTR PROJECT IS TO DEMONSTRATE THAT SILENCING OF ANGPTL3 BY GECTOSOME DELIVERY OF LWACAS13A/ANGPTL3 CRRNA IS EFFICACIOUS IN LOWERING LDL-C WITH ACCEPTABLE SAFETY PROFILE IN MICE. THE PROPOSED STRATEGY COMBINES TWO INNOVATIVE TECHNOLOGIES FOR POTENTIAL CLINICAL TRANSLATION. THE PROPOSED STUDIES ARE FEASIBLE BASED ON OUR PREVIOUS SUCCESS WITH GECTOSOME DELIVERY OF CRISPR RNP THAT CAUSES INACTIVATION OF PCSK9 IN MOUSE LIVER. ANGPTL3 IS PRIMARILY EXPRESSED IN HEPATOCYTES AND SECRETED INTO THE BLOODSTREAM. THE LIVER IS READILY ACCESSIBLE BY GECTOSOMES. LWACAS13A-MEDIATED RNA DEPLETION IS REVERSIBLE AND MAY HAVE FEWER SAFETY CONCERNS THAN GENE EDITING. WE WILL DETERMINE THE EFFICACY AND SAFETY OF ANGPTL3 SUPPRESSION BY LWACAS13A IN MICE AND THIS WORK IS NECESSARY FOR FURTHER STUDIES TO ADVANCE A POTENTIAL THERAPEUTIC SOLUTION FOR A RARE DISEASE.