A Stem Cell-Based Therapy To Treat Muscular Dystrophy

Muscular dystrophies, such as Duchenne's muscular dystrophy (DMD), are caused by genetic mutations that lead to a loss of expression of dystrophin, a key structural protein of muscle cells, which results in cell dysfunction. When this occurs the cells can no longer regenerate after injury, resulting in progressive muscle weakness and eventual death. One hope for therapy has been to replenish these defective cells with ESCs that produce normal dystrophin. However, this approach has been hampered by an inability to get ESCs to form muscle cells at appreciable levels.

Rita Perlingeiro and colleagues have overcome this hurdle and show functional recovery after injection of ESCs into a mouse model of DMD. The key to their success was to take advantage of the facts that almost all skeletal muscles have a similar embryonic origin and that muscle development depends on the transcription factor Pax3. As ESCs grown in a culture dish are not exposed to the embryonic environmental milieu that induces muscle differentiation, it might be possible to bypass this requirement by directly expressing Pax3, which orchestrates muscle development in the embryo, through genetic manipulations. This manipulation allows a muscle progenitor cell population to arise and in sufficient quantities to then use therapeutically in mice. The team was able to deliver these cells through the circulation, targeting many more muscle locations than by intramuscular injection, resulting in significantly improved muscle function. Finally, the use of the isolated muscle progenitor cells, owing to their partially differentiated state, did not result in tumor formation, which has previously hampered the therapeutic use of ESCs.

While the genetic manipulation of the ESCs disallows this technique to be used in the clinic at this point, future studies may point to ways of inducing Pax3 expression in human ESCs without the need of genetically modifying the cells.

Author contact:

Rita Perlingeiro (Department of Developmental Biology, University of Texas Southwestern, TX, USA)
E-mail: Rita.Perlingeiro@UTSouthwestern.edu

Abstract available online.

(C) Nature Medicine press release.

Message posted by: Trevor M. D'Souza