AAV vector-mediated microdystrophin expression in a relatively small percentage of mdx myofibers improved the mdx phenotype

被引:88
作者
Yoshimura, M
Sakamoto, M
Ikemoto, M
Mochizuki, Y
Yuasa, K
Miyagoe-Suzuki, Y
Takeda, S
机构
[1] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Mol Therapy, Kodaira, Tokyo 1878502, Japan
[2] Univ Tokyo, Grad Sch Med, Dept Neurol, Div Neurosci, Tokyo 1138655, Japan
关键词
Duchenne muscular dystrophy; gene therapy; adeno-associated virus vector; dystrophin; microdystrophin; skeletal muscle; mdx mouse; hypertrophy;
D O I
10.1016/j.ymthe.2004.07.025
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Duchenne muscular dystrophy (DMD) is a lethal disorder of skeletal muscle caused by mutations in the dystrophin gene. Adeno-associated virus (AAV) vector-mediated gene therapy is a promising approach to the disease. Although a rod-truncated microdystrophin gene has been proven to ameliorate dystrophic phenotypes, the level of microdystrophin expression required for effective gene therapy by an AAV vector has not been determined yet. Here, we constructed a recombinant AAV type 2 vector, AAV2-MCKDeltaCS1, expressing microdystrophin (DeltaCS1) under the control of a muscle-specific MCK promoter and injected it into TA muscles of 10-day-old and 5-week-old mdx mice. AAV2-MCKDeltaCS1-mediated gene transfer into 5-week-old mdx muscle resulted in extensive and long-term expression of microdystrophin and significantly improved force generation. Interestingly, 10-day-old injected muscle expressed microdystrophin in a limited number of myofibers but showed hypertrophy of microdystrophin-positive muscle fibers and considerable recovery of contractile force. Thus, we concluded that AAV2-MCKDeltaCS1 could be a powerful tool for gene therapy of DMD.
引用
收藏
页码:821 / 828
页数:8
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