Background: AAV mediated gene therapy holds great promise for the treatment of neuromuscular disorders. A critical barrier limiting the utility of AAV based therapy is off target adverse events, including particularly hepatotoxicity. Gene therapy for X-linked myotubular myopathy has epitomized the therapeutic dilemma, as an ongoing clinical trial of AAV8-MTM1 has shown incredible efficacy but has also resulted in fatal liver failure in 4 individuals. Pre clinical models have been poorly predictive of the side effects associated with AAV, and no liver concerns were identified in XLMTM mice treated with gene therapy. We recently demonstrated liver abnormalities in a zebrafish model of XLMTM, identifying that loss of MTM1 is sufficient to cause hepatobiliary disease.
Objectives: The goals of this study are to (1) evaluate the XLMTM mouse model for evidence of liver disease, (2) study the potential deleterious impact of AAV therapy on the hepatobiliary system in mice, and (3) test therapies for XLMTM associated hepatic injury.
Results: In exciting new data, using a modified diet paradigm, we now identify liver pathology (including cholestatic liver disease) in the XLMTM mouse model, with changes consistent with those described in XLMTM patients and Mtm1 deficient zebrafish. In addition, we show that AAV8 significantly increases susceptibility to liver cholestasis in XLMTM mice, and further demonstrate hepatobiliary abnormalities in wild type mice associated with AAV8 treatment. Lastly, we demonstrate rescue of the XLMTM liver phenotype with lipid nanoparticle delivery of MTM1, thereby identifying a potential treatment strategy to mitigate liver side effects in XLMTM patients.
Conclusions: In all, we present for the first time liver disease in the XLMTM mouse model and liver toxicity associated with AAV8 exposure. These data provide critical insight into the adverse events seen in human gene therapy studies, and set the stage for defining their pathomechanisms and identifying potential therapies.