The experiment did demonstrate that mGluR5 was a valid target for drug therapy. Other investigators have found that the interaction between FMRP and mGluRs is highly conserved in evolution, showing up in fruit flies and zebrafish in addition to mammals. This evolutionary conservation boosts confidence that pharmacologic approaches successful in animals may fare well in humans.

Trial Treatments

In 2005, Bear cofounded Seaside Therapeutics, Inc., a Cambridge, Massachusetts-based company dedicated to creating treatments to correct or improve the course of fragile X syndrome, autism, and other disorders of brain development. In July 2010, Seaside announced positive data from a randomized, placebo-controlled phase 2 study of pediatric patients with fragile X syndrome. Seaside used an experimental drug dubbed STX209, or arbaclofen, which inhibits glutamate signaling.

The trial showed that the drug reduced outbursts and tantrums and boosted sociability and communication. In September 2010, the company announced promising results from an “open label” phase 2 study of the drug in young patients with autism spectrum disorders, where the participants knew what drug they were receiving. These patients likewise were less irritable and less socially withdrawn.

The company has received federal regulatory approval to undertake larger trials of children with fragile X and autism. Meanwhile, another Seaside drug—STX107, which selectively blocks mGluR5—is in the pipeline. Other companies, including Novartis and Roche, are also working on glutamate inhibitors for fragile X.

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How would a treatment that could ease the symptoms of fragile X change people’s lives? “It’s like asking: What would it be like to have the best dream you could ever have come true?” says Katie Clapp, parent of a 21-year-old son with the disease. Clapp cofounded the FRAXA Research Foundation, which is dedicated to finding treatments and a cure for fragile X syndrome and has funded some of Bear’s work.

But Bear cautions that there may be limits to the mGluR theory. Most neurodevelopmental disorders are not diagnosed until well after symptoms begin, suggesting that doctors may not be able to give drug treatments early enough to stave off the worst effects of the disease, such as severe cognitive impairments. As Bear conceded in a 2008 paper in Neuropsychopharmacology, “derailment in brain development might be difficult to reverse retrospectively.” Some drugs may also carry intolerable side effects. In early clinical trials of glutamate inhibitors, a small proportion of patients suffered adverse events such as upper respiratory infections, sedation, and headache.

Despite these cautions, the recent clinical trials represent a dramatic shift in thinking. Scientists had long assumed that genetically based developmental disorders of the brain were permanent. But Bear has shown that treating the functional deficits with small molecule therapies may alter one’s fate in life, even if the gene remains unchanged. “Being born with a developmental brain disorder,” he says, “may not be an irrevocable sentence.”

And fragile X may just be the start. “The big splitting-the-deck question now,” he says, “is whether other rare, single-gene causes of autism—such as Rett syndrome and tuberous sclerosis complex—share similar characteristics with fragile X syndrome.” Even autism without a known cause may respond to the treatment. If so, mGluR5 blockers (or, with some disorders, enhancers) could have wide applications. Returning to a familiar metaphor, Bear calls this new line of thinking—and of hope—“a sea change.”

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