Gene Therapy Prolongs Survival and Restores Function in Murine and Canine Models of Myotubular Myopathy
- Fonction : Auteur
- PersonId : 1594963
- ORCID : 0000-0003-0731-3950
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- PersonId : 176491
- IdHAL : melissa-goddard
- ORCID : 0000-0003-1091-4888
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- Fonction : Auteur
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- Fonction : Auteur
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- PersonId : 1514182
- IdRef : 074447726
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- PersonId : 1050604
- IdHAL : a-buj-bello
- ORCID : 0000-0002-1098-3798
- IdRef : 231609841
Résumé
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.