Gene Therapy Prolongs Survival and Restores Function in Murine and Canine Models of Myotubular Myopathy

Abstract : Loss-of-function mutations in the myotubularin gene (MTM1) cause X-linked myotubular myopathy (XLMTM), a fatal, congenital pediatric disease that affects the entire skeletal musculature. Systemic administration of a single dose of a recombinant serotype 8 adeno-associated virus (AAV8) vector expressing murine myotubularin to Mtm1-deficient knockout mice at the onset or at late stages of the disease resulted in robust improvement in motor activity and contractile force, corrected muscle pathology, and prolonged survival throughout a 6-month study. Similarly, single-dose intravascular delivery of a canine AAV8-MTM1 vector in XLMTM dogs markedly improved severe muscle weakness and respiratory impairment, and prolonged life span to more than 1 year in the absence of toxicity or a humoral or cell-mediated immune response. These results demonstrate the therapeutic efficacy of AAV-mediated gene therapy for myotubular myopathy in small- and large-animal models, and provide proof of concept for future clinical trials in XLMTM patients.
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Martin Childers, Romain Joubert, Karine Poulard, Christel Moal, Robert Grange, et al.. Gene Therapy Prolongs Survival and Restores Function in Murine and Canine Models of Myotubular Myopathy. Science Translational Medicine, American Association for the Advancement of Science, 2014, 6 (220), pp.220ra10-220ra10. ⟨10.1126/scitranslmed.3007523⟩. ⟨hal-02180848⟩

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