TY - JOUR
T1 - Recombinant adeno-associated virus type 8-mediated extensive therapeutic gene delivery into skeletal muscle of α-sarcoglycan-deficient mice
AU - Nishiyama, Akiyo
AU - Ampong, Beryl Nyamekye
AU - Ohshima, Sachiko
AU - Shin, Jin Hong
AU - Nakai, Hiroyuki
AU - Imamura, Michihiro
AU - Miyagoe-Suzuki, Yuko
AU - Okada, Takashi
AU - Takeda, Shin'ichi
PY - 2008/7/1
Y1 - 2008/7/1
N2 - 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.
AB - 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.
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U2 - 10.1089/hum.2007.184
DO - 10.1089/hum.2007.184
M3 - Article
C2 - 18578595
AN - SCOPUS:47549106119
SN - 1043-0342
VL - 19
SP - 719
EP - 730
JO - Human Gene Therapy
JF - Human Gene Therapy
IS - 7
ER -