title: Micro-dystrophin cDNA ameliorates dystrophic phenotypes when introduced into mdx mice as a transgene.
abstract: 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.
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa Higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Sakamoto
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yuasa
authors.forename: Madoka
authors.initials: M
authors.lastname: Yoshimura
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yokota
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ikemoto
authors.forename: Misao
authors.initials: M
authors.lastname: Suzuki
authors.forename: George
authors.initials: G
authors.lastname: Dickson
authors.forename: Yuko
authors.initials: Y
authors.lastname: Miyagoe-Suzuki
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Takeda
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003402:Creatine Kinase / Q000097:blood; D018076:DNA, Complementary / Q000378:metabolism; D003964:Diaphragm / Q000378:metabolism; D016189:Dystrophin / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008856:Microscopy, Fluorescence; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000628:therapy; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012508:Sarcolemma / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes
chemical_list: D018076:DNA, Complementary; D016189:Dystrophin; D003402:Creatine Kinase