Long-term Skeletal Muscle Protection After Gene Transfer in a Mouse Model of LGMD-2D

Christina A Pacak; Glenn A Walter; Gabe Gaidosh; Nathan Bryant; Melissa A Lewis; Sean Germain; Cathryn S Mah; Kevin P Campbell; Barry J Byrne

doi:10.1038/sj.mt.6300246

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Long-term Skeletal Muscle Protection After Gene Transfer in a Mouse Model of LGMD-2D

Journal article

Open access

Peer reviewed

Long-term Skeletal Muscle Protection After Gene Transfer in a Mouse Model of LGMD-2D

Christina A Pacak, Glenn A Walter, Gabe Gaidosh, Nathan Bryant, Melissa A Lewis, Sean Germain, Cathryn S Mah, Kevin P Campbell and Barry J Byrne

Molecular therapy, Vol.15(10), pp.1775-1781

10/2007

DOI: 10.1038/sj.mt.6300246

PMID: 17653106

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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 T2-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.

Details

Title: Subtitle: Long-term Skeletal Muscle Protection After Gene Transfer in a Mouse Model of LGMD-2D
Creators: Christina A Pacak - Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, Florida, USA
Glenn A Walter - Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, Florida, USA
Gabe Gaidosh - Department of Physiology, Functional Genomics, University of Florida College of Medicine, Gainesville, Florida, USA
Nathan Bryant - Department of Physiology, Functional Genomics, University of Florida College of Medicine, Gainesville, Florida, USA
Melissa A Lewis - Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, Florida, USA
Sean Germain - Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, Florida, USA
Cathryn S Mah - Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, Florida, USA
Kevin P Campbell - HHMI, Department of Physiology, Biophysics, University of Iowa, Iowa City, Iowa, USA
Barry J Byrne - Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, Florida, USA
Resource Type: Journal article
Publication Details: Molecular therapy, Vol.15(10), pp.1775-1781
DOI: 10.1038/sj.mt.6300246
PMID: 17653106
NLM abbreviation: Mol Ther
ISSN: 1525-0016
eISSN: 1525-0024
Publisher: Elsevier Inc
Language: English
Date published: 10/2007
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984020889902771

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