Molecular Therapy
Volume 10, Issue 5, November 2004, Pages 821-828
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Article
AAV vector-mediated microdystrophin expression in a relatively small percentage of mdx myofibers improved the mdx phenotype

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Abstract

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-MCKΔCS1, expressing microdystrophin (ΔCS1) 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-MCKΔCS1-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-MCKΔCS1 could be a powerful tool for gene therapy of DMD.

Keywords

Duchenne muscular dystrophy
gene therapy
adeno-associated virus vector
dystrophin
microdystrophin
skeletal muscle
mdx mouse
hypertrophy

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