Long-term skeletal muscle protection after gene transfer in a mouse model of LGMD-2D.
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.
Pacak
Christina A
CA
Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
Walter
Glenn A
GA
Gaidosh
Gabe
G
Bryant
Nathan
N
Lewis
Melissa A
MA
Germain
Sean
S
Mah
Cathryn S
CS
Campbell
Kevin P
KP
Byrne
Barry J
BJ
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
D049031:Sarcoglycans