Abstract
Mice carrying mutations in both the dystrophin and utrophin genes die prematurely as a consequence of severe muscular dystrophy. Here, we show that intravascular administration of recombinant adeno-associated viral (rAAV) vectors carrying a microdystrophin gene restores expression of dystrophin in the respiratory, cardiac and limb musculature of these mice, considerably reducing skeletal muscle pathology and extending lifespan. These findings suggest rAAV vector–mediated systemic gene transfer may be useful for treatment of serious neuromuscular disorders such as Duchenne muscular dystrophy.
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Acknowledgements
We thank J. Sanes for the utrophin-null mice and Y. Tesch for assistance with initial setup of the dystrophic mouse breeding colony. This work was supported by a Development Grant from the Muscular Dystrophy Association (to P.G.), and by grants from the Muscular Dystrophy Association (to J.S.C.) and the US National Institutes of Health (to J.S.C., S.C.F. and M.E.A., and C.E.M.).
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Supplementary information
Supplementary Fig. 1
Restoration of dystrophin expression in muscles throughout the body of an adult dystrophin/utrophin double-knockout mouse following systemic administration of rAAV6-microdystrophin. (PDF 127 kb)
Supplementary Fig. 2
Systemic rAAV6-microdystrophin administration restores myocardial dystrophin expression. (PDF 114 kb)
Supplementary Video 1
Improved posture and muscularity in dystrophic mice following intravascular administration of rAAV6-microdystrophin. (MOV 1154 kb)
Supplementary Video 2
Enhanced mobility in dystrophic mice after systemic administration of rAAV6-microdystrophin. (MOV 2683 kb)
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Gregorevic, P., Allen, J., Minami, E. et al. rAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic mice. Nat Med 12, 787–789 (2006). https://doi.org/10.1038/nm1439
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DOI: https://doi.org/10.1038/nm1439
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