Duchenne muscular dystrophy remains an untreatable genetic disease that severely limits motility and life expectancy in affected children. The only animal model specifically reproducing the alterations in the dystrophin gene and the full spectrum of human pathology is the golden retriever dog model. Affected animals present a single mutation in intron 6, resulting in complete absence of the dystrophin protein, and early and severe muscle degeneration with nearly complete loss of motility and walking ability. Death usually occurs at about 1 year of age as a result of failure of respiratory muscles. Here we report that intra-arterial delivery of wild-type canine mesoangioblasts (vessel-associated stem cells) results in an extensive recovery of dystrophin expression, normal muscle morphology and function (confirmed by measurement of contraction force on single fibres). The outcome is a remarkable clinical amelioration and preservation of active motility. These data qualify mesoangioblasts as candidates for future stem cell therapy for Duchenne patients.
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We thank M. G. Roncarolo for helpful discussions; J. Chamberlain for the gift of the lentiviral vector expressing human microdystrophin; C. Drougard for technical assistance; X. Cauchois, I. Gruyer, S. Kouamé, E. Wembe and A. Brindejont and M. Carré at the Centre d'Elevage du Domaine des Souches for their care of the dogs; and N. Borenstein for the systemic delivery of cells. M.S. and G.C. thank P. Luban for a donation. This work was supported by grants from the Association Française contre les Myopathies, Telethon, the Muscular Dystrophy Association, the Parent Project Onlus, the European Community ‘Eurostemcell’, the Cariplo Foundation and the Italian Ministries of Health and Research. B.G.G. was supported by a 3+3 fellowship from the Centro Nacional de Investigationes Cardiovasculares, Spain. Author Contributions M.S. coordinated the work on cells with R.T. and M.G.C.D.; S.B. coordinated the work on dogs with N.G., J.L.T. and I.B.; R.B. and G.D.A. coordinated the physiology experiments with O.P., C.R. and P.M., who also developed, with S.M., the instrument to measure dog tetanic force; A.I. did the histology work; B.G.G. performed the homing experiments; L.P. and M.S. conducted the western blot analysis; M.G. did the immunology experiment; Y.T. and C.B. evaluated the clinical aspects of the work; G.C. coordinated the whole project.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
This file contains Supplementary Methods, Supplementary Figures and their legends. (PDF 24478 kb)
Untreated GRMD dog (MPG 5474 kb)
Valgus, GRMD dog treated with donor mesoangioblasts; inset movie, Valgus before the first treatment. (MPG 6378 kb)
Varus, GRMD dog treated with donor mesoangioblasts. (MPG 7875 kb)
Vampire, GRMD dog treated with autologous genetically modified mesoangioblasts. (MPG 2516 kb)
Azor, GRMD dog treated late with donor mesoangioblasts; inset movie, Azor before the first treatment. (MPG 7454 kb)
Azur, GRMD dog treated late with donor mesoangioblasts; inset movie, Azur before the first treatment. (MPG 4804 kb)
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Sampaolesi, M., Blot, S., D’Antona, G. et al. Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature 444, 574–579 (2006). https://doi.org/10.1038/nature05282
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