Abstract
DUCHENNE and Becker muscular dystrophy (DMD and BMD) are X-linked recessive diseases caused by defective expression of dystrophin1,2. The mdx mouse, an animal model for DMD, has a mutation that eliminates expression of the 427K muscle and brain isoforms of dystrophin1,3,4. Although these animals do not display overt muscle weakness or impaired movement, the diaphragm muscle of the mdx mouse is severely affected and shows progressive myofibre degeneration and fibrosis which closely resembles the human disease5,6. Here we explore the feasibility of gene therapy for DMD by examining the potential of a full-length dystrophin transgene to correct dystrophic symptoms in mdx mice. We find that expression of dystrophin in muscles of transgenic mdx mice eliminates the morphological and immunohistological symptoms of muscular dystrophy. In addition, overexpression of dystrophin prevents the development of the abnormal mechanical properties associated with dystrophic muscle without causing deleterious side effects. Our results provide functional evidence for the feasibility of gene therapy for DMD.
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References
Hoffman, E. P., Brown, R. H. Jr & Kunkel, L. M. Cell 51, 919–928 (1987).
Ahn, A. H. & Kunkel, L. M. Nature Genet. 3, 283–291 (1993).
Sicinski, P. et al. Science 244, 1578–1580 (1989).
Cox, G. A., Phelps, S. F., Chapman, V. M. & Chamberlain, J. S. Nature Genet. 4, 87–93 (1993).
Partridge, T. Neuropathol. appl. Neurobiol. 17, 353–363 (1991).
Stedman, H. H. et al. Nature 352, 536–539 (1991).
Lee, C. C., Pearlman, J. A., Chamberlain, J. S. & Caskey, C. T. Nature 349, 334–336 (1991).
Jaynes, J. B., Chamberlain, J. S., Buskin, J. N., Johnson, J. E. & Hauschka, S. D. Molec. cell Biol. 6, 2855–2864 (1986).
Johnson, J. E., Wold, B. J. & Hauschka, S. D. Molec. ceff. Biol. 9, 3393–3399 (1989).
Ervasti, J. M., Ohlendieck, K., Kahl, S. D., Gaver, M. G. & Campbell, K. P. Nature 345, 315–319 (1990).
Ervasti, J. M. & Campbell, K. P. Cell 66, 1121–1131 (1991).
Ibraghimov-Beskrovnaya, O. et al. Nature 355, 696–702 (1992).
Ohlendieck, K. & Campbell, K. P. J. Cell Biol. 115, 1685–1694 (1991).
Ohlendieck, K. et al. Neurology 43, 795–800 (1993).
Matsumura, K. et al. Nature 359, 320–322 (1992).
Matsumura, K., Ervasti, J. M., Ohlendieck, K., Kahl, S. & Campbell, K. P. Nature 360, 588–591 (1992).
Chapman, V. M., Miller, D. M., Armstrong, D. & Caskey, C. T. Proc. natn. Acad. Sci. U.S.A. 86, 1292–1296 (1989).
Watkins, S. C. Hoffman, E. P., Slayter, H. S. & Kunkel, L. M. Muscle Nerve 12, 861–868 (1989).
Wells, D. J. et al. Hum. molec. Genet. 1, 35–40 (1992).
Ragot, T. et al. Nature 361, 647–650 (1993).
Emery, A. E. H. Duchenne Muscular Dystrophy (Oxford Monog. Med. Genet. No. 15, Oxford Medical, 1987).
Hogan, B., Constantini, F. & Lacey, E. Manipulating the Mouse Embryo: A Laboratory Manual (Cold Spring Harbor Laboratory Press, New York, 1986).
Chamberlain, J. S., Phelps, S. F., Cox, G. A., Maichele, A. J. & Greenwood, A. D. in Molecular and Cell Biology of Muscular Dystrophy (ed. Partridge, T.) 167–189 (Chapman & Hall, London, 1993).
Ohlendieck, K. et al. Neuron 7, 499–508 (1991).
Ervasti, J. M., Kahl, S. D. & Campbell, K. P. J. biol. Chem. 266, 9161–9165 (1991).
Faulkner, J. A., Zerba, E. & Brooks, S. V. Am. J. Physiol. 259, 259–265 (1990).
Brooks, S. V. & Faulkner, J. A. J. Physiol. 436, 701–710 (1991).
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Cox, G., Cole, N., Matsumura, K. et al. Overexpression of dystrophin in transgenic mdx mice eliminates dystrophic symptoms without toxicity. Nature 364, 725–729 (1993). https://doi.org/10.1038/364725a0
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DOI: https://doi.org/10.1038/364725a0
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