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

Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy / Childers, Martin K.; Joubert, Romain; Poulard, Karine; Moal, Christelle; Grange, Robert W.; Doering, Jonathan A.; Lawlor, Michael W.; Rider, Branden E.; Jamet, Thibaud; Danièle, Nathalie; Martin, Samia; Rivière, Christel; Soker, Thomas; Hammer, Caroline; Van Wittenberghe, Laetitia; Lockard, Mandy; Guan, Xuan; Goddard, Melissa; Mitchell, Erin; Barber, Jane; Williams, J. Koudy; Mack, David L.; Furth, Mark E.; Vignaud, Alban; Masurier, Carole; Mavilio, Fulvio; Moullier, Philippe; Beggs, Alan H.; Buj Bello, Anna. - In: SCIENCE TRANSLATIONAL MEDICINE. - ISSN 1946-6234. - 6:220(2014), pp. 220ra10-220ra10. [10.1126/scitranslmed.3007523]

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

MAVILIO, Fulvio;
2014

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
2014
6
220
220ra10
220ra10
Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy / Childers, Martin K.; Joubert, Romain; Poulard, Karine; Moal, Christelle; Grange, Robert W.; Doering, Jonathan A.; Lawlor, Michael W.; Rider, Branden E.; Jamet, Thibaud; Danièle, Nathalie; Martin, Samia; Rivière, Christel; Soker, Thomas; Hammer, Caroline; Van Wittenberghe, Laetitia; Lockard, Mandy; Guan, Xuan; Goddard, Melissa; Mitchell, Erin; Barber, Jane; Williams, J. Koudy; Mack, David L.; Furth, Mark E.; Vignaud, Alban; Masurier, Carole; Mavilio, Fulvio; Moullier, Philippe; Beggs, Alan H.; Buj Bello, Anna. - In: SCIENCE TRANSLATIONAL MEDICINE. - ISSN 1946-6234. - 6:220(2014), pp. 220ra10-220ra10. [10.1126/scitranslmed.3007523]
Childers, Martin K.; Joubert, Romain; Poulard, Karine; Moal, Christelle; Grange, Robert W.; Doering, Jonathan A.; Lawlor, Michael W.; Rider, Branden E...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1074769
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