Preclinical Development of a Novel Gene Therapeutic for Inclusion Body Myositis

PROJECT SUMMARY. Gene therapy offers hope to patients with sporadic inclusion body myositis (IBM). This chronic rare disease exclusively affects older adults and results from inflammation rather than genetic mutations. Thus, it cannot be treated with gene replacement or gene editing approaches yet durable solutions like gene therapies are needed to address the progressive muscle degeneration. Such therapies could revolutionize the management of IBM patients especially as there are currently no approved treatments. AAVogen's long-term goal is to develop gene therapeutics for different muscle wasting diseases including IBM. Our current objective is to advance AVGN7 (rAAV6:Smad7), a gene therapeutic for enhancing striated muscle mass and function, to clinical trials for IBM. This is supported by the proposed IND-enabling preclinical studies and regulatory meetings that are required for IND filing with the FDA. We hypothesize that AVGN7 will significantly enhance muscle mass and function in IBM patients. Indeed, AVGN7 attenuates the actions of ActRIIb ligands (myostatin, activin, GDF11) by overexpressing SMAD7, which suppresses ActRIIb signaling inside the muscle cell. This in turn increases muscle protein synthesis, inhibits protein degradation and dramatically enhances muscle mass, strength and exercise capacity. It also completely prevents muscle wasting in different animal disease models including those with elevated inflammatory cytokines and muscle signaling. Most importantly, AVGN7 avoids the potentially very serious off-target effects reported for discontinued myostatin ligand traps and immunotherapeutics as AVGN7 uses a vector with high muscle tropism (AAV6) and the CK8 muscle-specific promoter. Mouse toxicology studies were recently completed and regulatory meetings with the FDA were held, although the FDA invited us to schedule additional meetings to discuss clinical and manufacturing plans. Thus, completing the following Milestones will satisfy critical requirements for an IND filing in preparation for first-in-man trials: (i) hold final pre-IND meeting with FDA, (ii) generate proof-of-concept data in a novel xenograft model of IBM and (iii) develop and validate anti-drug immune response and biodistribution assays. These studies are highly significant as they support development of a novel gene therapeutic for treating IBM, a rare and disabling disease that exclusively affects older adults. They are also highly innovative as the Milestone 2 studies utilize the most dynamic model for IBM drug testing ever developed and because AVGN7, unlike all other drugs in the space, was specifically designed for superior efficacy, safety and durability due to its ability to chronically attenuate multiple catabolic signals specifically in muscle. These signals are conserved in most if not all muscle wasting conditions, suggesting that our approach could be broadly effective in treating other age-related muscle wasting disease states.