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July 13, 2007
The development of an embryo is a very carefully regulated process. Genes that make proteins are very carefully "turned on," or "turned off." Failure of a gene to "turn on," or "turn off," can result in life-threatening consequences. Such is the case with Duchenne muscular dystrophy (DMD). However, at least for DMD because of new research one day all that may change.
Muscle development includes two proteins, utrophin and dystrophin. Soon after birth the production of utrophin slows down and dystrophin takes over as the main muscle protein.
Patients with DMD make dystrophin that is unable to function properly causing the muscles to fall apart. Because, utrophin is 80% identical to dystrophin in its gene sequence utrophin could fill in for dystrophin. Scientists realized that if they could keep utrophin production from being shut down they might have a shot at developing a therapy for MDD.
It turns out that utrophin is shut off by a protein called Ets-2 repressor factor (ERF) that sits on top of a small part of the eutrophin gene called the N-box. "We demonstrated that ERF significantly reduces or represses the activity of utrophin's N-box in muscle cells of mice," says senior author Tejvir Khurana, an associate professor at the University of Pennsylvania.
The scientists deleted the N-box portion of the utrophin gene and found that ERF was not able to turn off utrophin production. "This approach of repressing the repressor is medically relevant to treating muscular dystrophy in that one day we hope to be able to upregulate utrophin production," says Khurana.
"Dr. Khurana's work hints at what could be an important new drug target for DMD -- the more options we have with this disease, the better," says Sharon Hesterlee, vice president for translational research at the Muscular Dystrophy Association. "We've known for awhile that increasing utrophin expression can reduce symptoms of the disease, but it's very difficult to use a drug to increase gene activity. What's nice about this work is that now we can try to 'block a blocker' to get the same effect -- it's a more drug friendly approach.
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