Systemic Gene Replacement Therapy for Treatment of X-Linked MyoTubular Myopathy -XLMTM-

Martin K Childers, Romain Joubert, Karine Poulard, Christelle Moal, Robert W Grange, Jonathan A Doering, Michael W Lawlor, Branden E. Rider, Thibaud Jamet, Nathalie Danièle, Samia Martin, Christel Rivière, Thomas Soker, Caroline Hammer, Laetitia Van Wittenberghe, Mandy Lockard, Xuan Guan, Melissa Goddard, Erin Mitchell, Jane Barber, J. Koudy Williams, David L Mack, Mark E Furth, Alban Vignaud, Carole Masurier, Fulvio Mavilio, Philippe Moullier, Alan H Beggs, and Anna Buj-Bello

School of Medicine, University of Washington, US

Sci Transl Med.

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 lifespan to more than one year in the absence of toxicity, humoral and 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.

BIOSEB Instruments Used:
Infrared Actimeter (LE8815)

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