Recombinant adeno-associated virus type 8-mediated extensive therapeutic gene delivery into skeletal muscle of alpha-sarcoglycan-deficient mice.
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.
Nishiyama
Akiyo
A
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
Ampong
Beryl Nyamekye
BN
Ohshima
Sachiko
S
Shin
Jin-Hong
JH
Nakai
Hiroyuki
H
Imamura
Michihiro
M
Miyagoe-Suzuki
Yuko
Y
Okada
Takashi
T
Takeda
Shin'ichi
S
D000818:Animals; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000628:therapy*; D011995:Recombination, Genetic; D049031:Sarcoglycans / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012703:Serotyping; D014161:Transduction, Genetic; D016896:Treatment Outcome
D049031:Sarcoglycans