Research ArticleMuscular Dystrophy

Stem Cell–Mediated Transfer of a Human Artificial Chromosome Ameliorates Muscular Dystrophy

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Science Translational Medicine  17 Aug 2011:
Vol. 3, Issue 96, pp. 96ra78
DOI: 10.1126/scitranslmed.3002342

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Stem Cells Muscle in on the Action

The progressive muscle loss that is the hallmark of Duchenne muscular dystrophy (DMD) has proved very difficult to halt or reverse. Although the causative mutations of DMD were identified in the X-linked gene encoding dystrophin (a structural muscle protein) several decades ago, translating this genetic discovery into new treatments has been challenging. Most therapeutic strategies aim to use gene therapy to deliver the normal dystrophin gene to the dystrophic muscles of DMD patients. However, the dystrophin gene is too large to be carried by the viral vectors usually used in gene therapy and all muscles in the body would have to be injected with the vector and replacement gene. Now, Tedesco and colleagues combine stem cell therapy with a human artificial chromosome vector to overcome these two challenges in the mdx mouse model of DMD.

This team had previously identified a blood vessel stem cell called “mesoangioblast” that has the dual talents of being able to cross blood vessel walls and to differentiate into a variety of mesodermal cell types including muscle cells. Would these stem cells be able to deliver a replacement dystrophin gene to dystrophic muscles in the mdx mouse? Predicting that they would, Tedesco and colleagues used a human artificial chromosome vector engineered to carry the entire normal human dystrophin gene including the regulatory regions. They transferred the vector and its large cargo into mesoangioblasts isolated from mdx mice; then they injected the corrected mesoangioblasts directly into the dystrophic skeletal muscles of recipient immune-deficient mdx mice (to prevent reaction against the human protein). The authors showed that the transplanted mesoangioblasts were able to engraft in dystrophic muscles, express normal dystrophin, and produce functional muscle fibers with amelioration of dystrophic pathology. They also found that the transplanted mesoangioblasts contributed to the muscle satellite cell pool, which produces new muscle cells under normal conditions. Next, the authors showed that if they injected the corrected mesoangioblasts into the arterial circulation of mdx mice, the cells were able to cross blood vessel walls, home to dystrophic muscles and graft contribute to the formation of new dystrophin-expressing myofibers. The authors then showed that mice receiving the mesoangioblast transplants showed reduced fiber fragility, increased force, and greater motor capacity on treadmill and freewheel tests. Although there are still technical and regulatory hurdles to be overcome before this strategy can be used in DMD patients, stem cell–mediated transfer of the normal dystrophin gene using a human artificial chromosome shows promise as a treatment for this tragic and ultimately fatal disease.

Footnotes

  • Citation: F. S. Tedesco, H. Hoshiya, G. D’Antona, M. F. M. Gerli, G. Messina, S. Antonini, R. Tonlorenzi, S. Benedetti, L. Berghella, Y. Torrente, Y. Kazuki, R. Bottinelli, M. Oshimura, G. Cossu, Stem Cell–Mediated Transfer of a Human Artificial Chromosome Ameliorates Muscular Dystrophy. Sci. Transl. Med. 3, 96ra78 (2011).

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