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

James P. Greelish, Leonard T. Su, Edward B. Lankford, James M. Burkman, Haiyan Chen, Stephane K. Konig, Isabelle M. Mercier, Philippe R. Desjardins, Marilyn A. Mitchell, Xiang Guang Zheng, John Leferovich, Guang Ping Gao, Rita J. Balice-Gordon, James M. Wilson, Hansell H. Stedman

Research output: Contribution to journalArticlepeer-review

187 Scopus citations

Abstract

Limb-girdle muscular dystrophies 2C-F represent a family of autosomal recessive diseases caused by defects in sarcoglycan genes. The cardiomyopathic hamster is a naturally occurring model for limb-girdle muscular dystrophy caused by a primary deficiency in δ-sarcoglycan. 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.

Original languageEnglish (US)
Pages (from-to)439-443
Number of pages5
JournalNature Medicine
Volume5
Issue number4
DOIs
StatePublished - Apr 1999

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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