Preclinical Validation of AVGN7 for Treating Duchenne Muscular Dystrophy

PROJECT SUMMARYGene therapeutics offer hope to many patients with Duchenne muscular dystrophyDMDor with other neuromuscular degenerative diseasesAlthough successful in preclinical studiesnone of these drugs has ever restored striated muscle function to healthy non diseased levelsThis is also true for exonskipping drugs as both approaches delay muscle degenerationbut do not stimulate muscle regenerationThusthey cannot recover mobility in patients with advanced stages of the diseaseThis indicates that novel ancillary tools for enhancing muscle mass and function are needed to restore optimal muscle strengthOur objective is to validate the use of AVGNrAAVSMADa gene therapeutic for enhancing striated muscle mass and functionin the most commonly used small animal model for DMDthe mdx mouseWe hypothesize that AVGNwill significantly enhance striated muscle mass and function despite the compromised state of dystrophindeficient muscleThis is based on high profile preclinical studies demonstrating AVGNto attenuate ActRIIb signaling andtherebystimulate muscle protein synthesismuscle mass and strength and exercise and cardiac capacityAVGNalso prevents muscle wasting in animals with cancer by blocking muscle signaling pathways that are also activated in dystrophic muscleMost importantlythis therapeutic does not produce the serious offtarget effects that have compromised development of competingmyostatin attenuatingtechnologieswhich have either been shown to compromise blood vessel integrity or to possess this potentialOur milestones areito determine the minimal effective dose for enhancing dystrophic muscle mass and function andiito determine the long term efficacy of AVGNThe proposed approach is truly innovative as it utilizes a novel muscle specific gene therapeutic and state of the art tools to comprehensively assess muscle function at different scalesMoreoverAVGNhas the potential to address an enormous unmet market need that cannot be met by available or developing dystrophin replacement therapeuticsThese studies are highly significant as they will provide proof of concept data to be used in a future IND filing that in turnwill help advance a AVGNtowards clinical trials for DMDan FDA recognized orphan disease RELEVANCE TO PUBLIC HEALTHThe loss of striated muscle mass and function in patients with Duchenne muscular dystrophy significantly compromises quality of life and is ultimately fatalThe proposed studies will develop a novel gene therapy for preventing this loss and for complementing other emerging therapeutics that focus on restoring and stabilizing muscle structureThese studies will also advance the gene therapy towards an IND filing