Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy.
نویسندگان
چکیده
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.
منابع مشابه
Validity of a Neurological Scoring System for Canine X-Linked Myotubular Myopathy.
A simple clinical neurological test was developed to evaluate response to gene therapy in a preclinical canine model of X-linked myotubular myopathy (XLMTM). This devastating congenital myopathy is caused by mutation in the myotubularin (MTM1) gene. Clinical signs include muscle weakness, early respiratory failure, and ventilator dependence. A spontaneously occurring canine model has a similar ...
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[This corrects the article on p. 262 in vol. 3, PMID: 26605308.].
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ورودعنوان ژورنال:
- Science translational medicine
دوره 6 220 شماره
صفحات -
تاریخ انتشار 2014