Antagonizing fragile X

Illustration of chromosomes

Nearly three decades ago, an Emory-led international team identified fragile X syndrome as the most common inherited cause of intellectual disability.

Emory human genetics chair Stephen Warren and his colleagues discovered the mutated gene on the X chromosome that causes this disorder. The scientists helped develop a screening test for fragile X and have been studying it ever since.

But until now there has been no treatment. That may soon change. Along with four other medical centers, Emory is participating in a phase 2 clinical trial that will test a targeted drug therapy for fragile X syndrome. The randomized, double-blind study has 32 adult participants from 18 to 50 years, who have fragile X syndrome. A second study will continue testing the most effective dose of the drug against a placebo in 28 participants.

In the United States, fragile X syndrome is the most commonly known cause of autism, accounting for 2% to 5% of cases. It affects approximately 1 in 4,000 males and 1 in 8,000 females, in addition to many more unknown carriers of the mutation. A premutation of the gene is present in 1 in 800 males and 1 in 260 females.

Warren and others have learned that the genetic mutation inhibits the production of a protein, FMRP, which regulates the amount of other proteins produced in the brain. Scientists have since discovered that the absence of this protein leads to the overproduction of synaptic proteins triggered by the activity of mGluR5, a glutamate receptor that is part of the brain’s signaling mechanism. The absence of this protein results in the complex learning and behavior problems of fragile X syndrome.

“The drug we are testing is an mGluR5 antagonist, which puts a brake on the mGluR5 activity and may improve learning and cognition,” says Emory geneticist Jeannie Visootsak, the study’s principal investigator. “In mouse and fruit fly models, we were able to improve cognition with an mGluR5 antagonist.”

Last year, researchers conducted a phase 1 trial of the drug in adults without fragile X syndrome, noting no serious adverse events. The current trial will assess safety as well as efficacy.

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