AAV vector-mediated microdystrophin expression in a relatively small percentage of mdx myofibers improved the mdx phenotype.
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-MCKDeltaCS1, expressing microdystrophin (DeltaCS1) 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-MCKDeltaCS1-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-MCKDeltaCS1 could be a powerful tool for gene therapy of DMD.
Yoshimura
Madoka
M
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan.
Sakamoto
Miki
M
Ikemoto
Madoka
M
Mochizuki
Yasushi
Y
Yuasa
Katsutoshi
K
Miyagoe-Suzuki
Yuko
Y
Takeda
Shin'ichi
S
D000818:Animals; D003402:Creatine Kinase / Q000235:genetics; D000229:Dependovirus / Q000235:genetics*; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D051379:Mice; D018101:Mice, Inbred mdx; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000737:chemistry / Q000166:cytology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D012508:Sarcolemma / Q000737:chemistry / Q000378:metabolism
D016189:Dystrophin; D003402:Creatine Kinase