Micro-dystrophin cDNA ameliorates dystrophic phenotypes when introduced into mdx mice as a transgene

被引:94
作者
Sakamoto, M
Yuasa, K
Yoshimura, M
Yokota, T
Ikemoto, T
Suzuki, M
Dickson, G
Miyagoe-Suzuki, Y
Takeda, S
机构
[1] Natl Ctr Neurol & Psychiat, Dept Mol Therapy, Natl Inst Neurosci, Tokyo 1878502, Japan
[2] Saitama Med Sch, Dept Pharmacol, Moroyama, Saitama 3500495, Japan
[3] Kumamoto Univ, Div Transgen Technol, Ctr Anim Resources & Dev, Kumamoto 8608556, Japan
[4] Univ London, Ctr Biomed Sci, Sch Biol Sci, Egham TW20 0EX, Surrey, England
关键词
dystrophin; Duchenne muscular dystrophy; gene therapy; mdx mouse; mini-dystrophin; micro-dystrophin; rod domain; transgenic mice; adeno-associated virus vector;
D O I
10.1016/S0006-291X(02)00362-5
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The adeno-associated virus vector is a good tool for gene transfer into skeletal muscle, but the length of a gene that can be incorporated is limited. To develop a gene therapy for Duchenne muscular dystrophy, we generated a series of rod-truncated micro-dystrophin cDNAs: M3 (one rod repeat, 3.9 kb), AX11 (three rod repeats, 4.4 kb), and CS1 (four rod repeats, 4.9 kb). These micro-dystrophins, driven by a CAG promoter, were used to produce transgenic (Tg) mdx mice and all three micro-dystrophins were shown to localize at the sarcolemma together with the expression of dystrophin-associated proteins. Among them, CS1 greatly improved dystrophic phenotypes of mdx mice and contractile force of the diaphragm in particular was restored to the level of normal C57BL/10 mice. AX11 modestly ameliorated the dystrophic pathology, but, importantly, M3-Tg mdx mice still showed severe dystrophic phenotypes. These data suggest that the rod structure, and its length in particular, is crucial for the function of micro-dystrophin. (C) 2002 Elsevier Science (USA). All rights reserved.
引用
收藏
页码:1265 / 1272
页数:8
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