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

Akiyo Nishiyama, Beryl Nyamekye Ampong, Sachiko Ohshima, Jin Hong Shin, Hiroyuki Nakai, Michihiro Imamura, Yuko Miyagoe-Suzuki, Takashi Okada, Shin'ichi Takeda

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Autosomal recessive limb-girdle muscular dystrophy type 2D (LGMD 2D) is caused by mutations in the α-sarcoglycan gene (α-SG). The absence of α-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 α-SG gene therapy into α-SG-deficient muscle, we constructed rAAV serotypes 2 and 8 expressing the human α-SG gene under the control of the ubiquitous cytomegalovirus promoter (rAAV2-α-SG and rAAV8-α-SG). We compared the transduction profiles and evaluated the therapeutic effects of a single intramuscular injection of rAAVs into α-SG-deficient (Sgca-/-) mice. Four weeks after rAAV2 injection into the tibialis anterior (TA) muscle of 10-day-old Sgca-/- mice, transduction of the α-SG gene was localized to a limited area of the TA muscle. On the other hand, rAAV8-mediated α-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 α-SG transduction in LGMD 2D model animals paves the way for future clinical application.

Original languageEnglish (US)
Pages (from-to)719-730
Number of pages12
JournalHuman Gene Therapy
Volume19
Issue number7
DOIs
StatePublished - Jul 1 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Nishiyama, A., Ampong, B. N., Ohshima, S., Shin, J. H., Nakai, H., Imamura, M., Miyagoe-Suzuki, Y., Okada, T., & Takeda, S. (2008). Recombinant adeno-associated virus type 8-mediated extensive therapeutic gene delivery into skeletal muscle of α-sarcoglycan-deficient mice. Human Gene Therapy, 19(7), 719-730. https://doi.org/10.1089/hum.2007.184