Murine toxicology assessment of avgn7.2, a novel gene therapeutic for inclusion body myositis and other muscle wasting diseases.

Sporadic inclusion body myositis (IBM) is a highly debilitating muscle degenerative and rare disease of the middle aged and elderly. Because immunosuppressants fail to prevent muscle wasting in IBM patients and can even exacerbate it, drugs like AVGN7.2 are being developed to halt degeneration and to enhance muscle mass and function. AVGN7.2 is a novel gene therapeutic that attenuates activin receptors through muscle-specific human (h) SMAD7 expression and as part of its preclinical development, we performed a 91-day single-dose toxicology assessment of systemic safety, biodistribution and immunogenicity in accordance with Good Laboratory Practices. Standard physiological, ophthalmoscopic, hematological and serum chemistry examinations were performed and no adverse drug-related effects were detected at any dose (2.3E + 13, 7E + 13 and 2.1E + 14 vg/kg), resulting in a No Observed Adverse Effect Level of 2.1e14 vg/kg. Mice mounted early IgM and late IgG responses to the AAV6 capsid, but no response to the hSMAD7 protein. Vector biodistribution mirrored previously published patterns with liver followed by striated muscle having the highest levels, although overexpression of hSMAD7 and the S6RP biomarker only occurred in muscle. These data suggest that AVGN7.2 was well-tolerated even at doses known to elicit clinical toxicities with muscle-tropic AAV capsids other than AAV6.