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Long-term skeletal muscle protection after gene transfer in a mouse model of LGMD-2D.

AbstractLimb 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.
AuthorsChristina A Pacak, Glenn A Walter, Gabe Gaidosh, Nathan Bryant, Melissa A Lewis, Sean Germain, Cathryn S Mah, Kevin P Campbell, Barry J Byrne (Affiliation: Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, Florida 32610, USA.)
JournalMolecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 15 Issue 10 Pg. 1775-81 (Oct 2007) ISSN: 1525-0016 United States
PMID17653106 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Sarcoglycans
Topics
  • Animals
  • Dependovirus (genetics)
  • Gene Therapy
  • Genetic Vectors
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal (metabolism, pathology)
  • Muscular Dystrophies, Limb-Girdle (pathology, prevention & control)
  • Sarcoglycans (genetics)
  • Transfection