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
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
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.
Scolnick has not seen
the results of the Novartis trial, but was told of them and concluded that if
the drugs work in fragile X, “there’s nothing to say that they won’t work in
some cases of broader autism-spectrum disorders.”