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Early Promise for Mental Retardation Drug

A drug designed to fix the molecular defects in fragile X helps some patients.
April 30, 2010

Novartis is reporting early success for a new drug for fragile X syndrome, a disorder associated with mental retardation and autism, according to an article in The New York Times. Fragile X is the most common inherited form of mental retardation and the most common known cause of autism. Scientists hope that drugs that help fragile X will help other forms of autism as well. Intitial results in a small number of patients suggest the drug is most effective in people with an undisclosed biological marker.

A number of other companies are testing similar compounds, a prospect that has the autism community excited.

“I think that fragile X-targeted treatments are at the cutting edge of reversing cognitive deficits in individuals with neurodevelopmental disorders,” Randi Hagerman, medical director of the M.I.N.D. Institute at the University of California, Davis, told me when reporting a previous story on a similar drug. Hagerman consults with a number of companies, including Seaside, that are developing treatments for fragile X syndrome. “This could lead to reversing intellectual disabilities and behavioral problems with this disorder,” she says. “That is extremely exciting.”

“Just three years ago, I would have said that mental retardation is a disability needing rehab, not a disorder needing medication,” Dr. Thomas R. Insel, director of the National Institute of Mental Health, told the NYT. “Any positive results from clinical trials will be amazingly hopeful.”

According to the piece:

Dr. Mark C. Fishman, president of the Novartis Institutes for BioMedical Research, cautioned against too much optimism. The trial involved only a few dozen patients, only some of whom benefited from treatment. The drug is likely to be years away from being commercially available and could fail in further clinical trials, he said.

“We have been reluctant to make this public because we still need to do more experiments, do them correctly and in a bigger way,” Dr. Fishman said. “But our group feels pretty good about the data.”

If authenticated in further, larger trials, the results could also become a landmark in the field of autism research, since scientists speculated that the drug may help some patients with autism not caused by fragile X, perhaps becoming the first medicine to address autism’s core symptoms.

The Novartis trial, which began in 2008 in Europe with data analysis completed this year, was too brief to observe effects on basic intelligence. Instead, researchers measured a range of aberrant behaviors like hyperactivity, repetitive motions, social withdrawal and inappropriate speech. They gave one set of patients the drug and another a placebo, and after a few weeks switched treatments, with both doctors and patients unaware of which pill was which.

The results of the trial were something of a jumble until Novartis scientists noticed that patients who had a particular, undisclosed biological trait improved far more than others. “The bottom line is that we showed clear improvements in behavior,” Dr. Fishman said.

Novartis’s drug is in the same class as a compound being tested by start-up Seaside therapeutics. A piece I wrote on Seaside earlier this year explains how these drugs work:

The fragile X mutation blocks production of a protein called FMRP (fragile X mental retardation protein), whose normal task is to inhibit molecular activity at the connections between nerve cells. Loss of the protein appears to throws the system out of whack. “It’s like driving a car with your foot on the accelerator and no brake,” says Randall Carpenter, a physician and cofounder of Seaside. “There is too much activation of that pathway.”

In 2007, Mark Bear, a neuroscientist at MIT and cofounder of Seaside, and his collaborators discovered that they could reverse the deficits caused by the fragile X mutation in mice by turning down the activity of a receptor called metabotropic glutamate receptor 5 (mGluR5), found on the surface of brain cells. By doing this they effectively added a new brake to the system. Animals engineered to produce 50 percent less of this receptor suffered fewer seizures–a hallmark of fragile X–and had fewer brain abnormalities compared to mice producing the full amount of the receptor.

Dozens of academic labs across the globe have since shown that small molecules designed to block the activity of mGluR5 have the same effect, reducing abnormalities in mice with the fragile X mutation. Those abnormalities include seizures, atypical rates of protein synthesis, and other molecular glitches. While it’s not yet clear if there is a critical window during development for giving the drug, adult animals still benefit from the treatment. “These compounds have made remarkable changes in animal models of fragile X, rescuing abnormal synaptic connections,” says Hagerman. “We’re very hopeful it will do the same for humans.”

Seaside, which licensed some of these compounds from Merck, has just finished initial safety studies of one candidate. (Large pharmaceutical companies have been developing these molecules, called mGluR5 antagonists, for years for a variety of diseases, including schizophrenia and Parkinson’s disease. None have yet been approved for human use, however.) Seaside aims to begin studies in people with fragile X later this year or early in 2011.

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