AAV Vector-Mediated Microdystrophin Expression in a
Relatively Small Percentage of mdx Myofibers Improved the mdx Phenotype
Molecular Therapy, 2004
Madoka Yoshimura, Miki Sakamoto,
Madoka Ikemoto, Yasushi Mochizuki, Katsutoshi Yuasa, Yuko Miyagoe-Suzuki, and
Shin’ichi Takeda - Japan
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-MCKDCS1, expressing microdystrophin (DCS1)
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-MCKDCS1-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-MCKDCS1 could be a powerful tool for gene therapy of DMD.