Journal
MOLECULAR THERAPY
Volume 15, Issue 10, Pages 1775-1781Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.mt.6300246
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Funding
- NHLBI NIH HHS [P01 HL059412, U01 HL69748, R01 HL78670, P01 HL59412] Funding Source: Medline
- NIAMS NIH HHS [AR47292] Funding Source: Medline
- NIDDK NIH HHS [P01 DK58327] Funding Source: Medline
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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.
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