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 Citations (Scopus)

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
Externally publishedYes

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Sarcoglycans
Dependovirus
Skeletal Muscle
Muscles
Sarcoglycanopathies
Genes
Sarcolemma
Therapeutics
Intramuscular Injections
Therapeutic Uses
Cytomegalovirus
Genetic Therapy
Extremities
Animal Models
Pathology
Mutation
Injections

ASJC Scopus subject areas

  • Genetics

Cite this

Recombinant adeno-associated virus type 8-mediated extensive therapeutic gene delivery into skeletal muscle of α-sarcoglycan-deficient mice. / Nishiyama, Akiyo; Ampong, Beryl Nyamekye; Ohshima, Sachiko; Shin, Jin Hong; Nakai, Hiroyuki; Imamura, Michihiro; Miyagoe-Suzuki, Yuko; Okada, Takashi; Takeda, Shin'ichi.

In: Human Gene Therapy, Vol. 19, No. 7, 01.07.2008, p. 719-730.

Research output: Contribution to journalArticle

Nishiyama, A, Ampong, BN, Ohshima, S, Shin, JH, 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, vol. 19, no. 7, pp. 719-730. https://doi.org/10.1089/hum.2007.184
Nishiyama, Akiyo ; Ampong, Beryl Nyamekye ; Ohshima, Sachiko ; Shin, Jin Hong ; Nakai, Hiroyuki ; Imamura, Michihiro ; Miyagoe-Suzuki, Yuko ; Okada, Takashi ; Takeda, Shin'ichi. / Recombinant adeno-associated virus type 8-mediated extensive therapeutic gene delivery into skeletal muscle of α-sarcoglycan-deficient mice. In: Human Gene Therapy. 2008 ; Vol. 19, No. 7. pp. 719-730.
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