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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Harper, S.Q. et al. Nat. Med. 8, 253–261 (2002).
Gregorevic, P. et al. Nat. Med. 10, 828–834 (2004).
Bulfield, G. et al. Proc. Natl. Acad. Sci. USA 81, 1189–1192 (1984).
Stedman, H.H. et al. Nature 352, 536–539 (1991).
Grady, R.M. et al. Cell 90, 729–738 (1997).
Deconinck, A.E. et al. Cell 90, 717–727 (1997).
Gozal, D. Pediatr. Pulmonol. 29, 141–150 (2000).
Petrof, B.J. et al. Proc. Natl. Acad. Sci. USA 90, 3710–3714 (1993).
Rafael, J.A. et al. Nat. Genet. 19, 79–92 (1998).
Collins, K.A. et al. Physiol. Genomics 13, 227–239 (2003).
Greelish, J.P. et al. Nat. Med. 5, 439–443 (1999).
Yue, Y. et al. Circulation 108, 1626–1632 (2003).
Hawkins, D. & Bey, M. J. Biomech. 30, 63–70 (1997).
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.).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
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)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1439
This article is cited by
-
Evaluation of the dystrophin carboxy-terminal domain for micro-dystrophin gene therapy in cardiac and skeletal muscles in the DMDmdx rat model
Gene Therapy (2022)
-
In vivo genome editing in mouse restores dystrophin expression in Duchenne muscular dystrophy patient muscle fibers
Genome Medicine (2021)
-
Dystrophin R16/17 protein therapy restores sarcolemmal nNOS in trans and improves muscle perfusion and function
Molecular Medicine (2019)
-
Production of adeno-associated virus vectors for in vitro and in vivo applications
Scientific Reports (2019)
-
Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models
Nature Medicine (2019)