Can we enlist substitute genes to fight muscular dystrophy

arch supports the idea that if you can crank up the production of utrophin, you will compensate for the lack of dystrophin.

In the article, Khurana and his colleagues describe how specific intercellular signals, such as heregulin, set into motion a series of reactions within the cell that lead to the activation of the utrophin gene. In cultured muscle cells, the researchers demonstrated how heregulin ultimately switches on Sp1, a transcription factor, which then binds to a specific region of the DNA that drives the utrophin gene. Once attached to DNA, Sp1, along with another heregulin-stimulated transcription factor called GABP /, attracts the cellular machinery responsible for transcribing genes into proteins.

The utrophin protein bears many functional similarities to dystrophin, although it is expressed in more types of cell tissue. At the neuromuscular junction, the two proteins work as part of the complex network of molecules that sustain muscle tissue through wear and tear. In healthy muscle tissue, dystrophin works as a sort of shock absorber to keep the cell membrane from tearing apart during muscle contraction. Since it is so similar to dystrophin, utrophin can also function as this molecular shock absorber, although not as well.

The idea that utrophin has a protective effect against DMD has been gaining favor as researchers looked deeper into the causes of the disease. In fact, studies have shown that disease progresses slowly in the first two weeks after birth in dystrophin deficient mice, since the levels of utrophin are still quite high, but much more quickly in mice that lack both the utrophin and dystrophin genes.

These findings will help define targets for stimulating the muscle cells native mechanisms into producing more utrophin, said Khurana. And while a substitute isnt always as good as the original, in this case good enough may well result in a substantial improvement. Contributors to this study include Ma

Contact: Greg Lester
University of Pennsylvania School of Medicine

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