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Recombinant adeno-associated virus type 8-mediated extensive therapeutic gene delivery into skeletal muscle of alpha-sarcoglycan-deficient mice.

Abstract
Autosomal recessive limb-girdle muscular dystrophy type 2D (LGMD 2D) is caused by mutations in the alpha-sarcoglycan gene (alpha-SG). The absence of alpha-SG results in the loss of the SG complex at the sarcolemma and compromises the integrity of the sarcolemma. To establish a method for recombinant adeno-associated virus (rAAV)-mediated alpha-SG gene therapy into alpha-SG-deficient muscle, we constructed rAAV serotypes 2 and 8 expressing the human alpha-SG gene under the control of the ubiquitous cytomegalovirus promoter (rAAV2-alpha-SG and rAAV8-alpha-SG). We compared the transduction profiles and evaluated the therapeutic effects of a single intramuscular injection of rAAVs into alpha-SG-deficient (Sgca(-/-)) mice. Four weeks after rAAV2 injection into the tibialis anterior (TA) muscle of 10-day-old Sgca(-/-) mice, transduction of the alpha-SG gene was localized to a limited area of the TA muscle. On the other hand, rAAV8-mediated alpha-SG expression was widely distributed in the hind limb muscle, and persisted for 7 months without inducing cytotoxic and immunological reactions, with a reversal of the muscle pathology and improvement in the contractile force of the Sgca(-/-) muscle. This extensive rAAV8-mediated alpha-SG transduction in LGMD 2D model animals paves the way for future clinical application.
AuthorsAkiyo Nishiyama, Beryl Nyamekye Ampong, Sachiko Ohshima, Jin-Hong Shin, Hiroyuki Nakai, Michihiro Imamura, Yuko Miyagoe-Suzuki, Takashi Okada, Shin'ichi Takeda
JournalHuman gene therapy (Hum Gene Ther) Vol. 19 Issue 7 Pg. 719-30 (Jul 2008) ISSN: 1557-7422 [Electronic] United States
PMID18578595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Sarcoglycans
Topics
  • Animals
  • Dependovirus (classification, genetics)
  • Genetic Therapy (methods)
  • Genetic Vectors
  • Humans
  • Mice
  • Mice, Knockout
  • Muscle Contraction (physiology)
  • Muscle, Skeletal (metabolism, pathology, virology)
  • Muscular Dystrophies, Limb-Girdle (therapy)
  • Recombination, Genetic
  • Sarcoglycans (deficiency, genetics, metabolism)
  • Serotyping
  • Transduction, Genetic
  • Treatment Outcome

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