Rescue of Skeletal Muscles of γ-Sarcoglycan- Deficient Mice with Adeno-Associated Virus-Mediated Gene Transfer

Laurence Cordier*, Andrew A. Hack, Marion O. Scott, Elisabeth R. Barton-Davis, Guang Ping Gao, James M. Wilson, Elizabeth M. McNally, H. Lee Sweeney

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

In humans, a subset of cases of Limb-girdle muscular dystrophy (LGMD) arise from mutations in the genes encoding one of the sarcoglycan (α, β, γ, or δ) subunits of the dystrophin-glycoprotein complex. While adeno-associated virus (AAV) is a potential gene therapy vector for these dystrophies, it is unclear if AAV can be used if a diseased muscle is undergoing rapid degeneration and necrosis. The skeletal muscles of mice lacking γ-sarcoglycan (gsg-/- mice) differ from the animal models that have been evaluated to date in that the severity of the skeletal muscle pathology is much greater and more representative of that of humans with muscular dystrophy. Following direct muscle injection of a recombinant AAV [in which human γ-sarcoglycan expression is driven by a truncated muscle creatine kinase (MCK) promoter/enhancer], we observed significant numbers of muscle fibers expressing γ-sarcoglycan and an overall improvement of the histologic pattern of dystrophy. However, these results could be achieved only if injections into the muscle were prior to the development of significant fibrosis in the muscle. The results presented in this report show promise for AAV gene therapy for LGMD, but underscore the need for intervention early in the time course of the disease process.

Original languageEnglish (US)
Pages (from-to)119-129
Number of pages11
JournalMolecular Therapy
Volume1
Issue number2
DOIs
StatePublished - Feb 2000

Keywords

  • Creatine kinase promoter
  • Gene therapy
  • Limb-girdle muscular dystrophy

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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