An experimental drug succeeded in a small clinical trial in bringing about what the researchers called substantial improvements in the behaviours associated with retardation and autism in people with fragile X syndrome, the most common inherited cause of these mental disabilities.

The surprising results, disclosed in a recent interview by Novartis, the Swiss pharmaceutical giant that makes the drug, grew out of three decades of painstaking genetic research, leaps in the understanding of how the brain works, the advocacy of families who refused to give up, and a chance meeting between two scientists who mistakenly showed up at the same conference.
“Just three years ago, I would have said that mental retardation is a disability needing rehab, not a disorder needing medication,” said Dr. Thomas R. Insel, director of the National Institute of Mental Health, who was told of the Novartis trial results. “Any positive results from clinical trials will be amazingly hopeful.”

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,” 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.

One child in 5,000 is born with fragile X syndrome, with mental effects ranging from mild learning disabilities to retardation so profound that sufferers do not speak, and physical effects that include elongated faces, prominent jaws, big ears, and enlarged testes. It mostly affects boys and earned its name because, under a microscope, one arm of the X chromosome seems nearly broken, with part hanging by a thread.

The gene for fragile X was discovered in 1991. Work since then has found that fragile X patients seem to experience an overload of unchecked synaptic noise – synapses being the junctions between brain neurons. The Novartis drug and others like it are intended to lower the volume of this noise so memory formation and high-level thinking can take place, allowing children to develop normally.

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 behaviours 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 behaviour,” Fishman said.

Geraldine Dawson, chief science officer at Autism Speaks, the world’s largest autism advocacy organization, said that a growing body of research suggests that the many genetic causes of autism all seem to affect synapses, suggesting that a treatment for one form of the disease might help others.
“The exciting thing about these results is that it is our hope that these same medications may have similar positive benefits for people with autism who don’t have fragile X syndrome,” Dawson said.

Between 10 percent and 15 percent of autism cases result from fragile X syndrome or some other known genetic defect. While fragile X is the most common inherited cause of mental retardation, Down syndrome – which also causes retardation – is more common but is not inherited.

The Novartis trial results were not published or peer reviewed, and for commercial reasons Fishman refused to divulge many details. Dr. Luca Santarelli, head of neuroscience at Roche, confirmed that Roche is in the midst of testing a similar medicine in fragile X patients at four sites in the United States.

“So far we like what we see,” Santarelli said in his only characterization of their study.

One reason for the euphoria surrounding the Novartis trial is that it was seen as an especially difficult test of the drug’s effects. For ethical reasons, Novartis tested the drug only in adults. But the company and outside researchers believe that such compounds may prove most effective in young children, whose brains are far more likely to respond rapidly when barriers to learning are removed.

“This is perhaps the most promising therapeutic discovery ever for a gene-based behavioural disease,” said Dr. Edward M. Scolnick, former research chief at Merck and now director of the Stanley Center for Psychiatric Research at the Broad Institute at Harvard and the Massachusetts Institute of Technology.