Uncovering the immunological determinants of progressive liver disease in X-linked Myotubular Myopathy 2260077

Abstract Introduction X-linked myotubular myopathy (XLMTM) is a fatal cogenital neuromuscular disease caused by mutations in MTM1. While adeno-associated virus (AAV) gene therapy has shown promising outcomes in the first clinical trial for XLMTM, its progress has been halted by unexplained and often lethal hepatotoxicity. XLMTM is hallmarked by an accumulation of phosphatidylinositol 3-phosphate, which is a known regulator of macrophage phagocytic activities. Given that Mtm1 is also highly expressed in resident liver myeloid cells, we hypothesized that MTM1 deficiency disrupts intrinsic myeloid regulatory processes, creating a hyperinflammatory microenvironment that sensitizes the liver to gene therapy-associated injury. Methods We compared wild-type (WT) and Mtm1 knock-out (KO) mice challenged with H1N1 infection or bacterial endotoxemia (LPS) starting at postnatal day 21 to unmask latent immunopathology. Plasma cytokines analysis, liver histopathology and immunophenotyping were performed at the clinical endpoint. Results Following H1N1 infection, KO mice exhibited reduced survival (within a week post infection) and heightened liver inflammation characterized by F4/80+ myeloid cell infiltration alongside a systemic cytokine storm. This hyper-inflammatory state was starkly highlighted during endotoxemia, where a sublethal dose of LPS for WT mice was fatal to all KO mice within four hours and associated with a 2-fold increase in plasma IL-6 concentrations. This extreme sensitivity to immune stimuli is consistent with the predicted hyper-inflammatory state of myeloid sentinels due to the lack of MTM1. Conclusion The absence of MTM1 heightens the susceptibility to severe, immune-mediated inflammatory damage during early life, underscoring the urgent need for immunomodulatory co-therapies. Future work using macrophage models will serve as a crucial platform to test targeted immunomodulatory therapies designed to prevent this lethal inflammatory response and improve the safety of AAV gene therapy for XLMTM patients. Funding Source CIHR Topic Categories Immune Mechanisms of Human Disease (HUM)