. Gene therapeutics offer hope to many patients with Duchenne muscular dystrophy (DMD) or with other neuromuscular degenerative diseases. Although successful in preclinical studies, none of these drugs has ever restored striated muscle function to healthy non-diseased levels. This is also true for exon- skipping drugs as both approaches delay muscle degeneration, but do not stimulate muscle regeneration. Thus, they cannot recover mobility in patients with advanced stages of the disease. This indicates that novel ancillary tools for enhancing muscle mass and function are needed to restore optimal muscle strength. Our objective is to validate the use of AVGN7 (rAAV6:SMAD7), a gene therapeutic for enhancing striated muscle mass and function, in the most commonly used small animal model for DMD, the mdx mouse. We hypothesize that AVGN7 will significantly enhance striated muscle mass and function despite the compromised state of dystrophin- deficient muscle. This is based on high profile preclinical studies demonstrating AVGN7 to attenuate ActRIIb signaling and, thereby, stimulate muscle protein synthesis, muscle mass and strength and exercise and cardiac capacity. AVGN7 also prevents muscle wasting in animals with cancer by blocking muscle signaling pathways that are also activated in dystrophic muscle. Most importantly, this therapeutic does not produce the serious off- target effects that have compromised development of competing ?myostatin attenuating? technologies, which have either been shown to compromise blood vessel integrity or to possess this potential. Our milestones are (i) to determine the minimal effective dose for enhancing dystrophic muscle mass and function and (ii) to determine the long-term efficacy of AVGN7. The 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 scales. Moreover, AVGN7 has the potential to address an enormous unmet market need that cannot be met by available or developing dystrophin replacement therapeutics. These studies are highly significant as they will provide proof-of-concept data to be used in a future IND filing that in turn, will help advance a AVGN7 towards clinical trials for DMD, an FDA-recognized orphan disease.
TO PUBLIC HEALTH. The loss of striated muscle mass and function in patients with Duchenne muscular dystrophy significantly compromises quality of life and is ultimately fatal. The 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 structure. These studies will also advance the gene therapy towards an IND filing.
