Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy. Sci Transl Med 2014 Jan 22;6(220):220ra10
Date
01/24/2014Pubmed ID
24452262Pubmed Central ID
PMC4105197DOI
10.1126/scitranslmed.3007523Scopus ID
2-s2.0-84893427190 (requires institutional sign-in at Scopus site) 128 CitationsAbstract
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.
Author List
Childers MK, Joubert R, Poulard K, Moal C, Grange RW, Doering JA, Lawlor MW, Rider BE, Jamet T, Danièle N, Martin S, Rivière C, Soker T, Hammer C, Van Wittenberghe L, Lockard M, Guan X, Goddard M, Mitchell E, Barber J, Williams JK, Mack DL, Furth ME, Vignaud A, Masurier C, Mavilio F, Moullier P, Beggs AH, Buj-Bello AAuthor
Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsDependovirus
Diaphragm
Disease Models, Animal
Dogs
Genetic Therapy
Genetic Vectors
Genotype
HEK293 Cells
Humans
Male
Mice
Mice, Knockout
Muscle Contraction
Muscle Weakness
Mutation
Myopathies, Structural, Congenital
Protein Tyrosine Phosphatases, Non-Receptor