title: Long-term skeletal muscle protection after gene transfer in a mouse model of LGMD-2D.
abstract: Limb girdle muscular dystrophy (LGMD) describes a group of inherited diseases resulting from mutations in genes encoding proteins involved in maintaining skeletal muscle membrane stability. LGMD type-2D is caused by mutations in alpha-sarcoglycan (sgca). Here we describe muscle-specific gene delivery of the human sgca gene into dystrophic muscle using an adeno-associated virus 1 (AAV1) capsid and creatine kinase promoter. Delivery of this construct to adult sgca(-/-) mice resulted in localization of the sarcoglycan complex to the sarcolemma and a reduction in muscle fiber damage. Sgca expression prevented disease progression as observed in vivo by T(2)-weighted magnetic resonance imaging (MRI) and confirmed in vitro by decreased Evan's blue dye accumulation. The ability of recombinant AAV-mediated gene delivery to restore normal muscle mechanical properties in sgca(-/-) mice was verified by in vitro force mechanics on isolated extensor digitorum longus (EDL) muscles, with a decrease in passive resistance to stretch as compared with untreated controls. In summary, AAV/AAV-sgca gene transfer provides long-term muscle protection from LGMD and can be non-invasively evaluated using magnetic resonance imaging.
authors.affiliation: Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Pacak
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Walter
authors.forename: Gabe
authors.initials: G
authors.lastname: Gaidosh
authors.forename: Nathan
authors.initials: N
authors.lastname: Bryant
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Lewis
authors.forename: Sean
authors.initials: S
authors.lastname: Germain
authors.forename: Cathryn S
authors.initials: CS
authors.lastname: Mah
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000473:pathology / Q000517:prevention & control*; D049031:Sarcoglycans / Q000235:genetics; D014162:Transfection
chemical_list: D049031:Sarcoglycans