AAV8 gene therapy and dietary insults together precipitate cholestatic liver disease in a mouse model of X-linked myotubular myopathy - PubMed
4 days ago
- #gene therapy
- #XLMTM
- #liver disease
- AAV8 gene therapy and dietary insults together cause cholestatic liver disease in a mouse model of X-linked myotubular myopathy (XLMTM).
- XLMTM patients treated with AAV8-driven MTM1 gene replacement experienced fatal liver injury not predicted by preclinical models.
- Mtm1 knockout mice fed purified ingredient diets showed liver dysfunction similar to human clinical presentations, including elevated transaminases and bile acid abnormalities.
- MTM1 plays a role in maintaining hepatocyte structure and bile salt export pump localization.
- Liver-specific deletion of Mtm1 replicated many liver dysfunction features, indicating a liver-autonomous role.
- AAV8 gene therapy increased cholestasis susceptibility in global KO mice and induced liver injury in wild-type mice.
- Lipid nanoparticle MTM1 gene replacement prevented key liver abnormalities in global KO mice.
- The study provides insights into AAV-associated toxicity mechanisms and potential therapeutic interventions.