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Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno-associated viral vector

Nature Medicine volume 5, pages 439–443 (1999)Cite this article

Abstract

Limb-girdle muscular dystrophies 2C–F represent a family of autosomal recessive diseases caused by defects in sarcoglycan genes1. The cardiomyopathic hamster is a naturally occurring model for limb-girdle muscular dystrophy caused by a primary deficiency in δ-sarcoglycan2,3,4,5. We show here that acute sarcolemmal disruption occurs in this animal model during forceful muscle contraction. A recombinant adeno-associated virus vector encoding human δ-sarcoglycan conferred efficient and stable genetic reconstitution in the adult cardiomyopathic hamster when injected directly into muscle. A quantitative assay demonstrated that vector-transduced muscle fibers are stably protected from sarcolemmal disruption; there was no associated inflammation or immunologic response to the vector-encoded protein. Efficient gene transduction with rescue of the sarcoglycan complex in muscle fibers of the distal hindlimb was also obtained after infusion of recombinant adeno-associated virus into the femoral artery in conjunction with histamine-induced endothelial permeabilization. This study provides a strong rationale for the development of gene therapy for limb-girdle muscular dystrophy.

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Figure 1: Acute sarcolemmal disruption in clustered myocytes of BIO 14.6 hamster skeletal muscle after forceful contraction.
Figure 2: Sarcoglycan complex rescue.
Figure 3: Gene transfer across the endothelial barrier: Histamine and papaverine transiently increase permeability.
Figure 4: Rescue of the sarcoglycan complex in muscles throughout the adult BIO 14.

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Acknowledgements

Acknowledgments These studies were supported in part by grants from the National Institutes of Health (5PO1AR/NS43648) and the Muscular Dystrophy Association. L.S. is a research fellow of the American Heart Association. S.K. is a research fellow of the Association Francaise contre les Myopathies.

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Author notes

  1. J.P.G. & L.T.S. contributed equally to this study.

Authors and Affiliations

  1. Department of Surgery, University of Pennsylvania Health System, Philadelphia, 19104, Pennsylvania, USA

    James P. Greelish, Leonard T. Su, James M. Burkman, Haiyan Chen, Stephane K. Konig, Isabelle M. Mercier, Philippe R. Desjardins, Marilyn A. Mitchell, Xiang guang Zheng & Hansell H. Stedman

  2. Department of Medicine, University of Pennsylvania Health System, Philadelphia, 19104, Pennsylvania, USA

    Edward B. Lankford, John Leferovich & James M. Wilson

  3. Department of Neuroscience, University of Pennsylvania Health System, Philadelphia, 19104, Pennsylvania, USA

    Rita J. Balice-Gordon

  4. Department of Molecular and Cellular Engineering, University of Pennsylvania Health System, Philadelphia, 19104, Pennsylvania , USA

    Guang Ping Gao & James M. Wilson

  5. Institute for Human Gene Therapy, University of Pennsylvania Health System, Philadelphia, 19104, Pennsylvania, USA

    Guang Ping Gao, James M. Wilson & Hansell H. Stedman

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  1. James P. Greelish
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Correspondence to Hansell H. Stedman.

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Greelish, J., Su, L., Lankford, E. et al. Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno-associated viral vector. Nat Med 5, 439–443 (1999). https://doi.org/10.1038/7439

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