title: Adeno-associated virus vector-mediated minidystrophin gene therapy improves dystrophic muscle contractile function in mdx mice.
abstract: Duchenne muscular dystrophy (DMD) is the most common disabling and lethal genetic muscle disorder, afflicting 1 of every 3500 males. Patients with DMD experience progressive muscle degeneration and weakness and succumb to respiratory or cardiac failure by their early twenties. No treatment is currently available for DMD. Mutations in the dystrophin gene result in lack of a functional dystrophin protein in striated muscle, which induces instability in the muscle cell membrane leading to persistent muscle injury after contraction. We have previously created novel minidystrophin genes and demonstrated that adeno-associated virus (AAV)-mediated intramuscular delivery of the minigenes effectively ameliorated mdx dystrophic histopathology and led to normal cell membrane integrity for more than 1 year. In this paper, we investigated whether AAV-minidystrophin could also improve mdx muscle contractile function. Two-month-old adult male mdx mice, with established muscular dystrophy, were given a single-dose injection of an AAV-minidystrophin vector in the tibialis anterior (TA) muscle of one leg, with the untreated contralateral leg used as a control. The treated TA muscle showed both (1) a significant increase in isometric force generation and (2) a significant increase in resistance to lengthening activation-induced muscle force decrements. We conclude that AAV-minidystrophin gene treatment is effective in improving mdx muscle contractile function.
authors.affiliation: Division of Neonatology and Developmental Biology, Department of Pediatrics, Magee-Women's Research Institute, Pittsburgh, PA 15213, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Watchko
authors.forename: Terry
authors.initials: T
authors.lastname: O'Day
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Liqiao
authors.initials: L
authors.lastname: Zhou
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D000229:Dependovirus; D016189:Dystrophin / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology; D018482:Muscle, Skeletal / Q000502:physiology; D020388:Muscular Dystrophy, Duchenne / Q000628:therapy*
chemical_list: D016189:Dystrophin