Attempts to develop gene therapy for Duchenne muscular dystrophy (DMD) have been complicated by the enormous size of the dystrophin gene. We have performed a detailed functional analysis of dystrophin structural domains and show that multiple regions of the protein can be deleted in various combinations to generate highly functional mini- and micro-dystrophins. Studies in transgenic mdx mice, a model for DMD, reveal that a wide variety of functional characteristics of dystrophy are prevented by some of these truncated dystrophins. Muscles expressing the smallest dystrophins are fully protected against damage caused by muscle activity and are not morphologically different from normal muscle. Moreover, injection of adeno-associated viruses carrying micro-dystrophins into dystrophic muscles of immunocompetent mdx mice results in a striking reversal of histopathological features of this disease. These results demonstrate that the dystrophic pathology can be both prevented and reversed by gene therapy using micro-dystrophins.
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We thank M. Grounds and S. Hauschka for helpful discussions; R. Maniker, S. Kellogg and C. Hassett for technical assistance; Y. Yue for production of rAAV micro-dystrophins; the University of Michigan transgenic animal model core; and all members of our laboratory for advice and encouragement. This work was supported by grants from the Muscular Dystrophy Association (to J.S.C., J.F.E. and D.D.) and the National Institutes of Health (to J.S.C., J.F.E. and S.V.B.).
The former institution of J.S.C., the University of Michigan, has filed for a patent application on the concept of micro-dystrophin cDNAs and their use in therapy. This application is pending.
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Harper, S., Hauser, M., DelloRusso, C. et al. Modular flexibility of dystrophin: Implications for gene therapy of Duchenne muscular dystrophy. Nat Med 8, 253–261 (2002). https://doi.org/10.1038/nm0302-253
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