Stable Restoration of the Sarcoglycan Complex in Dystrophic Muscle Perfused With Histamine and a Recombinant Adeno-Associated Viral Vector

Nat Med. 1999 Apr;5(4):439-43. doi: 10.1038/7439.

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 delta-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 delta-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Membrane Permeability
  • Cricetinae
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / therapeutic use*
  • Dependovirus / genetics
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Histamine / therapeutic use*
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / therapeutic use*
  • Muscular Dystrophy, Animal / therapy*
  • Perfusion
  • Rats
  • Rats, Inbred F344
  • Recombinant Proteins / therapeutic use
  • Sarcoglycans
  • Sarcolemma / pathology

Substances

  • Cytoskeletal Proteins
  • Membrane Glycoproteins
  • Recombinant Proteins
  • Sarcoglycans
  • Histamine