AV8 gene therapy and environmental exposure precipitate cholestatic liver disease in a mouse model of X-linked myotubular myopathy

AAV-associated hepatotoxicity has been observed in patients, with poor concordance between preclinical studies and clinical outcomes. Gene therapy for X-linked myotubular myopathy (XLMTM) has epitomized this therapeutic dilemma, as an AAV8-MTM1 clinical trial has shown efficacy but also fatal liver failure in a subset of individuals. In the present study, we address this conundrum, and demonstrate for the first time in mice that early-life nutrition and AAV exposure can promote liver injury. Specifically, XLMTM mice fed a purified-diet manifest liver dysfunction that mirrors what is seen in patients. AAV8-therapy increases this susceptibility, and additionally promotes liver injury in wild-type mice. Notably, non-viral lipid nanoparticle delivery of MTM1 rescues the XLMTM liver phenotype, offering a potential treatment strategy to mitigate liver consequences in patients. Together, these data provide critical insight into the adverse events seen in viral-gene therapy studies and set the stage for defining their pathomechanisms and identifying potential therapies. In this study, we employed the widely used Mtm1-/- knockout (KO) mouse to investigate the susceptibility of XLMTM mice to cholestasis. Mtm1 KO mice fed a semi-purified ingredient diet (as opposed to Chow) develop liver dysfunction that closely resembles the biochemical and histological features of cholestatic liver disease thus far described in XLMTM patients.