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

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)...

Full description

Saved in:
Bibliographic Details
Published in:Biochemical and biophysical research communications 2002-05, Vol.293 (4), p.1265-1272
Main Authors: Sakamoto, Miki, Yuasa, Katsutoshi, Yoshimura, Madoka, Yokota, Toshifumi, Ikemoto, Takaaki, Suzuki, Misao, Dickson, George, Miyagoe-Suzuki, Yuko, Takeda, Shin'ichi
Format: Article
Language:English
Subjects:
Adeno-associated virus vector
Animals
Blotting, Western
Creatine Kinase - blood
Diaphragm - metabolism
DNA, Complementary - metabolism
Duchenne muscular dystrophy
Dystrophin
Dystrophin - biosynthesis
Dystrophin - genetics
Dystrophin - metabolism
Gene therapy
Humans
Immunohistochemistry
mdx Mouse
Mice
Mice, Inbred C57BL
Mice, Inbred mdx
Micro-dystrophin
Microscopy, Fluorescence
Mini-dystrophin
Muscle Fibers, Skeletal - metabolism
Muscle, Skeletal - metabolism
Muscular Dystrophy, Duchenne - therapy
Phenotype
Promoter Regions, Genetic
Rod domain
Sarcolemma - metabolism
Time Factors
Transgenes
Transgenic mice
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0006-291X
1090-2104
DOI:10.1016/S0006-291X(02)00362-5