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.
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Authors | Akiyo Nishiyama, Beryl Nyamekye Ampong, Sachiko Ohshima, Jin-Hong Shin, Hiroyuki Nakai, Michihiro Imamura, Yuko Miyagoe-Suzuki, Takashi Okada, Shin'ichi Takeda |
Journal | Human gene therapy
(Hum Gene Ther)
Vol. 19
Issue 7
Pg. 719-30
(Jul 2008)
ISSN: 1557-7422 [Electronic] United States |
PMID | 18578595
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
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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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