Novel Drug for Fragile X Could Treat Disorder Cause Instead of Symptoms


Fragile X Syndrome (FXS) is the most common cause of inherited mental impairment and the most common known cause of autism or autistic-like behaviors. Most of the current medications available only treat symptoms such as seizures and mood instability, however, researchers from Rush University Medical Center have developed a drug that could treat the underlying disorder.

Fragile X affects 1 in 4000 males and 1 in 6000 females of all races and ethnic groups.

In an early Phase II trial of 30 Fragile X patients, a drug known as AFQ056, made by Novartis Pharmaceuticals, helped improve symptoms by blocking the activity of mGluR5 (metabotropic glutamate receptor 5). This receptor protein, found on brain cells, is involved in most aspects of normal brain function, including the regulation of the strength of brain connections.

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Patients with Fragile X have a mutation in a single gene (Fragile X Mental Retardation-1 or FMR-1) that prevents a protein called FMRP from being made. Because FMRP normally acts as a blocker for brain cell pathways activated by mGluR5, if it is missing, these pathways are overactive, resulting in abnormal brain connections. The result is behavioral and cognitive impairment.


Patients in the study with a specific mutation, a fully methylated gene that was completely shut down resulting in no FMR protein in the blood or brain and displaying severe Fragile X symptoms, showed the most improvement in behavior, hyperactivity, and inappropriate speech with AFQ056 compared to a placebo. Those with only partially methylated genes, and therefore only partially active FMR1, did not respond as well.

This “DNA Fingerprint” could be used as a test for which patients can benefit most from the new drug.

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“This is an exciting development,” said Dr. Elizabeth Berry-Kravis, a pediatric neurologist and director of the Fragile X Clinic and Research Program at Rush. “This drug could be a model for treatment of other disorders such as autism.”
Dr. Berry-Kravis notes that the drug was well-tolerated among the study participants and there were no safety problems found. Previous studies of mGluR5-blocking drugs found only moderate side effects such as fatigue.

A larger study of the drug is now underway that will recruit 160 patients worldwide and test the effects of a longer period of treatment. The research will test for methylation of the FMR1 gene and patients will take the drug for 3 months.

Source Reference:
S. Jacquemont, A. Curie, V. des Portes, M. G. Torrioli, E. Berry-Kravis, et al. Epigenetic Modification of the FMR1 Gene in Fragile X Syndrome Is Associated with Differential Response to the mGluR5 Antagonist AFQ056. Science Translational Medicine, 2011; 3 (64): 64ra1 DOI: 10.1126/scitranslmed.3001708