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rAAV vector-mediated sarcogylcan gene transfer in a hamster model for limb girdle muscular dystrophy

Gene Therapy volume 6, pages 74–82 (1999)Cite this article

Abstract

The limb girdle muscular dystrophies (LGMD) are a genetically and phenotypically heterogeneous group of degenerative neuromuscular diseases. A subset of the genetically recessive forms of LGMD are caused by mutations in the four muscle sarcoglycan genes (α, β, γ and δ). The coding sequences of all known sarcoglycan genes are smaller than 2 kb, and thus can be readily packaged in recombinant adeno-associated virus (rAAV) vectors. Previously, we have demonstrated highly efficient and sustained transduction in mature muscle tissue of immunocompetent animals with rAAV vectors. In this report, we utilize recombinant AAV containing the δ-sarcoglycan gene for genetic complementation of muscle diseases using a δ- sarcoglycan-deficient hamster model (Bio14.6). We show efficient delivery and widespread expression of δ-sarcoglycan after a single intramuscular injection. Importantly, rAAV vector containing the human δ-sarcoglycan cDNA restored secondary biochemical deficiencies, with correct localization of other sarcoglycan proteins to the muscle fiber membrane. Interestingly, restoration of α-, as well as β-sarcoglycan was homogeneous and properly localized throughout transduced muscle, and appeared unaffected by dramatic overexpression of δ-sarcoglycan in the cytoplasm of some myofibers. These results support the feasibility of rAAV vector’s application to treat LGMD by means of direct in vivo gene transfer.

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Authors and Affiliations

  1. Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    J Li, D Dressman, Y P Tsao, E P Hoffman & X Xiao

  2. National Cardiovascular Center, Osaka, Japan

    A Sakamoto

  3. Department of Human Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    E P Hoffman

  4. Department of Pediatrics,, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    E P Hoffman

  5. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    E P Hoffman

  6. National Defense Medical Center, Taipei, Taiwan

    Y P Tsao

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  2. D Dressman
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Li, J., Dressman, D., Tsao, Y. et al. rAAV vector-mediated sarcogylcan gene transfer in a hamster model for limb girdle muscular dystrophy. Gene Ther 6, 74–82 (1999). https://doi.org/10.1038/sj.gt.3300830

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