Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 6, Issue 220, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3007523
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Funding
- Association Francaise contre les Myopathies (France)
- Muscular Dystrophy Association (United States)
- Myotubular Trust (UK)
- Genopole d'Evry (France)
- INSERM (France)
- Region d'Alsace (France)
- U.S. NIH [P50 NS040828, R01 AR044345, K08 AR059750, R21 AR064503, R01 HL115001]
- Anderson Family Foundation
- Joshua Frase Foundation
- Where There's a Will There's a Cure and Peter Khuri Myopathy Research Foundation
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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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