Promise Seen in Drug for Retardation Syndrome

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http://www.nytimes.com/2010/04/30/health/research/30fragile.html?hp

An experimental drug succeeded in a small clinical trial in bringing about what

the researchers called substantial improvements in the behaviors 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 an interview this week 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.

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,¡¨ 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.

One child in five thousand 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 ¡X

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 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.

Told of the results, two parents of a fragile X patient were euphoric.

¡§This is what we have been working for and hoping for since our son was

diagnosed with fragile X 17 years ago,¡¨ said Clapp, president and

co-founder of the Fraxa Research Foundation, a nonprofit organization dedicated

to financing fragile X research. ¡§This may be the key to solving the mystery of

autism and other developmental disorders.¡¨

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,¡¨ Dr. 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 ¡X which also causes retardation ¡X

is more common but is not inherited.

The Novartis trial results were not published or peer reviewed, and for

commercial reasons Dr. 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,¡¨ Dr. 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

behavioral disease,¡¨ said Dr. 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.

Dr. 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.¡¨

An Unlikely Beginning

The roots for the Novartis results began in 1982 when T. Warren, then a

graduate student in genetics at Michigan State University, was looking for a job

and something to research. A friend told him about fragile X and, with the same

reflection he might use to pick a novel for a long flight, he decided that he

wanted to find the gene that caused it.

¡§I had no idea how hard this would be,¡¨ Dr. Warren said. Nine years later, Dr.

Warren, then at Emory University, was part of an international team that won a

fierce competition by isolating the gene. The discovery was front-page news

around the world, and experts predicted that widespread fetal testing and

therapies were in the offing.

The predictions were premature because, like most of genetic research,

discovering how the flawed gene caused disease was far harder than anticipated

and required multiple leaps in neurology and biology. And even with those, much

remains mysterious.

Fragile X is caused by a genetic stutter in which a portion of the gene gets

repeated like a scratched album. With each subsequent generation, the number of

repeats tends to rise. So if a mother has 10 repeats, her child might have 11 or

12. For reasons that are not well understood, however, this process of repeat

amplification can suddenly go haywire. So mothers who have 55 or more repeats

tend to have children with hundreds.

In anyone with 200 or more repeats, the body shuts off the gene. Since genes are

used to make proteins, this genetic silencing means the encoded protein is never

made. The absence of this protein in cells causes the wide-ranging effects of

fragile X syndrome. Those with 55 to 200 repeats are considered carriers, and

recent research shows they can have severe neurological declines late in life

that mimic Alzheimer¡¦s and Parkinson¡¦s.

Many geneticists would have moved on to other research topics after finding a

disorder¡¦s underlying gene. But Dr. Warren met affected children and their

parents. Instead of family pictures, Dr. Warren¡¦s desk displays a framed photo

of a fragile X chromosome.

¡§I could not imagine telling someone like Clapp that we were not going to

pursue this research anymore,¡¨ he said.

So he kept on. Years of work by him and others found that the protein missing in

those with fragile X normally seems to act as a sort of traffic cop at brain

synapses, helping to stop or slow brain signaling at crucial intervals. It does

this by sopping up the genetic instructions needed to produce proteins that

encourage brain signaling. Regulating this flow of electronic pulses across the

brain is crucial for the brain¡¦s ability to learn and mature.

Dr. Warren was puzzling over how to recreate that synaptic traffic cop when,

because of a scheduling conflict, he showed up in 2001 at the wrong scientific

conference and happened to sit next to Mark F. Bear, a neuroscience professor at

M.I.T. who had just given a presentation about compounds that seemed to work in

synapses to speed the creation of proteins ¡X including the one missing in

fragile X patients.

The two got to talking and decided to collaborate. They found that if Dr. Bear

reverse-engineered his compounds, they seemed to slow brain transmissions.

Instead of a traffic cop, the brain would get speed bumps. Not ideal, but

perhaps adequate in lowering the synaptic noise enough to encourage learning and

the moderation of the kind of synaptic traffic jams that in fragile X children

can lead to seizures.

Sure enough, mice, fish and fruit flies that through genetic engineering were

made to have fragile X seemed to become normal when given Dr. Bear¡¦s compound.

The Novartis compound is a member of the same drug family.

¡§We have been promising for a long time that unlocking the molecular basis for

hereditary diseases would lead to dramatic therapeutic advances, and that

promise is finally coming true,¡¨ said Dr. Francis S. , director of the

National Institutes of Health, in discussing the science leading up to the

trial. ¡§But it has not been easy.¡¨

A Search for Treatment

A hundred years ago, Clapp would have died giving birth to Andy, her child

with fragile X.

¡§Andy¡¦s head was too big to get out without a C-section, he would have killed

me, and that would have taken care of the fragile X gene,¡¨ she said.

But Ms. Clapp and Andy did survive. And despite going to some of the best

hospitals in the country, four years would pass before Andy¡¦s condition was

properly diagnosed.

When a doctor finally thought to do a fragile X test, Ms. Clapp and her husband,

Dr. Tranfaglia ¡X both Harvard graduates with post-graduate degrees ¡X

researched the disease and came to two conclusions: fragile X was potentially

treatable; and only about five researchers in the world were working toward a

cure.

¡§And I thought, what if all five walk across the street at the same time and

get hit by a Mack truck?¡¨ Ms. Clapp said. ¡§That is not going to get us

there.¡¨

So the two started the Fraxa Research Foundation. Remarkably, their efforts seem

to be paying off and may finally offer hope not only to those who with fragile X

but to carriers like Andy¡¦s sister, .

¡§I¡¦ve always known my kids have a chance of having it,¡¨ , 18, said in a

recent visit to the family¡¦s house. ¡§But I¡¦m not going to have kids for at

least 10 years anyway, and they¡¦ll have a cure for by then.¡¨

She paused, looked at her mother and said: ¡§You¡¦ve got 10 years.¡¨