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Sci Transl Med. 2014 Jan 22;6(220):220ra10. doi: 10.1126/scitranslmed.3007523.

Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy.

Author information

1
Department of Rehabilitation Medicine, School of Medicine, University of Washington, Campus Box 358056, Seattle, WA 98109, USA.

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.

PMID:
24452262
PMCID:
PMC4105197
DOI:
10.1126/scitranslmed.3007523
[Indexed for MEDLINE]
Free PMC Article

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