Abstract
DUCHENNE muscular dystrophy (DMD) is a severe, progressive muscle-wasting disease that causes cardiac or respiratory failure1,2 and results in death at about 20 years of age. Replacement of the missing protein, dystrophin, using myoblast transfer in humans or viral/liposomal delivery in the mouse DMD model is inefficient and short-lived3,4. One alternative approach to treatment would be to upregulate the closely related protein, utrophin5,6, which might be able to compensate for the dystrophin deficiency in all relevant muscles7,8. As a first step to this approach, we have expressed a utrophin transgene at high levels in the dystrophin-deficient mdx mouse. Our results indicate that high expression of the utrophin transgene in skeletal and diaphragm muscle can markedly reduce the dystrophic pathology. These data suggest that systemic upregulation of utrophin in DMD patients may lead to the development of an effective treatment for this devastating disorder.
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References
Hoffman, E. P. Brain Pathol. 6, 49–61 (1996).
Emery, A. E. H. Duchenne Muscular Dystrophy (Oxford Monogr. Med. Genet. No. 24, Oxford Univ. Press, 1993).
Partridge, T. A. & Davies, K. E. Br. Med. Bull. 51, 123–137 (1995).
Morgan, J. E. Hum. Gene Ther. 5, 165–173 (1994).
Love, D. R. et al. Nature 339, 55–58 (1989).
Tinsley, J. M. et al. Nature 360, 591–393 (1992).
Tinsley, J. M. & Davies, K. E. Neuromuscul. Discord. 3, 537–539 (1993).
Hoffman, E. P. Nature Genet. 8, 311–312 (1994).
Phelps, S. F. et al. Hum. Mol. Genet. 4, 1251–1258 (1995).
Wells, D. J. et al. Hum. Mol. Genet. 4, 1245–1250 (1995).
Cox, G. A. et al. Nature 264, 725–729 (1993).
Tinsley, J. M., Blake, D. J., Zuellig, R. A. & Davies, K. E. Proc. Natl Acad. Sci.USA 91, 8307–8313 (1994).
Blake, D. J., Tinsley, J. M. & Davies, K. E. Brain Pathol. 6, 37–47 (1996).
Sicinski, P. et al. Science 244, 1578–1580 (1989).
Rafael, J. A. et al. Hum. Mol. Genet. 3, 1725–1733 (1994).
Matsumara, K. & Campbell, K. P. Muscle Nerve 17, 2–15 (1994).
Campbell, K. P. Cell 80, 675–679 (1995).
Stedman, H. H. et al. Nature 352, 536–539 (1991).
Collins, A. F. et al. Blood 85, 43–49 (1995).
Dover, G. J., Brusilow, S. & Charache, S. Blood 84, 339–343 (1994).
Brennan, K. J. & Hardeman, E. C. J. Biol. Chem. 268, 719–725 (1993).
Muscat, G. O. & Kedes, L. Mol. Cell. Biol. 7, 4089–4099 (1987).
Hogan, B., Constantini, F. & Lacey, E. Manipulating the Mouse Embryo: A Laboratory Manual (Cold Spring Harbour Lab. Press, New York, 1986).
Nhuyen, T. M. et al. J. Cell Biol. 115, 1695–1700 (1991).
Sherratt, T. G., Vulliamy, T. & Strong, P. N. Biochem. J. 287, 755–759 (1992).
Roberds, S. L., Anderson, R. D., Ibraghimov-Breskrovnaya, O. & Campbell, K. P. J. Biol. Chem. 268, 23739–23742 (1993).
Ibraghimov-Breskrovnaya, O. et al. Nature 355, 696–702 (1992).
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Tinsley, J., Potter, A., Phelps, S. et al. Amelioration of the dystrophic phenotype of mdx mice using a truncated utrophin transgene. Nature 384, 349–353 (1996). https://doi.org/10.1038/384349a0
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DOI: https://doi.org/10.1038/384349a0
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