Adenovirus-mediated dystrophin minigene transfer improves muscle strength in adult dystrophic (MDX) mice.
Duchenne muscular dystrophy (DMD) and murine X-linked muscular dystrophy (mdx) are both due to absence of the subsarcolemmal protein dystrophin. Recombinant adenovirus vectors (AdV) are considered a promising means for delivering a functional dystrophin gene to muscle. However, the usefulness of AdV for this purpose is limited by vector toxicity as well as immune-mediated elimination of infected fibers. In addition, studies to date of AdV-mediated dystrophin gene transfer have either failed to examine effects on muscle strength or been performed in immunologically immature neonatal animals with little baseline abnormality of force-generating capacity. In the present study, AdV-mediated dystrophin gene transfer was performed in adult mdx mice with pre-existent dystrophic pathology and muscle weakness. The main findings are as follows: (1) acute myofiber toxicity and gene transfer efficiency are both AdV dose-dependent, such that the therapeutic margin of safety is fairly narrow; (2) immunosuppressive therapy (FK506) prevents immune-mediated elimination of dystrophin-positive fibers but not the dose-dependent toxic effects; (3) at the optimal vector dosage and with effective immunosuppression, AdV-mediated dystrophin minigene transfer is capable of alleviating the loss of force-generating capacity as well as histopathological evidence of disease progression normally seen in adult mdx muscles over a 2-month period. These findings have important implications for the eventual application of AdV-mediated dystrophin gene transfer in DMD patients.
Yang
L
L
Respiratory Division, Royal Victoria Hospital, Montreal, Quebec, Canada.
Lochmuller
H
H
Luo
J
J
Massie
B
B
Nalbantoglu
J
J
Karpati
G
G
Petrof
B J
BJ
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003964:Diaphragm / Q000473:pathology / Q000503:physiopathology; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use*; D007165:Immunosuppression Therapy; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*
D016189:Dystrophin