February 22, 2010

Decades of fragile X research lead to targeted treatment trials

Emory scientists have led research on fragile X syndrome since it was first identified nearly three decades ago as the most common inherited cause of intellectual disability. In 1991, Emory human genetics chair Stephen Warren led a team that discovered the mutated gene on the X chromosome. Emory scientists helped develop a screening test for fragile X and have been studying it ever since, but until now there has been no treatment.

Now after two decades, a possible treatment is in sight. Emory is participating, along with four other medical centers, in a Phase II clinical trial testing the first targeted drug therapy for fragile X syndrome.

Fragile X syndrome affects approximately 1 in 4,000 males and 1 in 8,000 females in the United States, in addition to many more carriers of the mutation. A premutation of the gene is present in 1 in 800 males and 1 in 260 females.

The randomized, double-blind, placebo-controlled clinical study is being conducted in 32 adult participants, ages 18 to 50, with fragile X syndrome. A second study will continue testing the most effective dose against a placebo in 28 participants. In addition to Emory, the study sites are Rush Medical Center, Indiana University Medical Center, Vanderbilt University Medical Center, and the University of California, Davis, Medical Center.

Warren and others have learned that the genetic mutation inhibits the production of a protein, FMRP, which leads to the overproduction of certain signaling proteins in the brain. This results in the complex learning and behavior problems of fragile X syndrome.

“The increased activity of the signaling protein mGluR5 acts like a car that keeps driving without a brake,” says Emory geneticist Jeannie Visootsak, principal investigator of the study. “The drug we are testing is an mGluR5 antagonist, which puts a brake on the mGluR5 activity and may improve learning and cognition. In mouse and fruit fly models, we were able to improve cognition with an mGluR5 antagonist.”

A phase I trial of the drug was conducted last year in adults without fragile X syndrome, and no serious adverse events were noted. The current trial will assess safety as well as efficacy.

The clinical trial is sponsored by Roche Pharmaceuticals.

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