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Promise Seen in Drug for Retardation Syndrome

By _GARDINER HARRIS_

(http://topics.nytimes.com/top/reference/timestopics/people/h/gardiner_harris/in\

dex.html?inline=nyt-per)

_http://www.nytimes.http://wwhttp://www.nyhttp://wwhttp://wwwhttp_

(http:///)

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_

(http://health.nytimes.com/health/guides/disease/autism/overview.html?inline=nyt\

-classifier) in people with

_fragile X syndrome_

(http://health.nytimes.com/health/guides/disease/fragile-x-syndrome/overview.htm\

l?inline=nyt-classifier) , the most common inherited

cause of these mental disabilities.

The surprising results, disclosed in an interview this week by _Novartis_

(http://www.novartis.com/) , 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_

(http://health.nytimes.com/health/guides/disease/mental-retardation/overview.htm\

l?i

nline=nyt-classifier) is a disability needing rehab, not a disorder

needing medication,†said Dr. R. Insel, director of the_National

Institute

of Mental Health_ (http://www.nimh.nih.gov/index.shtml) , who was told of

the _Novartis_

(http://topics.nytimes.com/top/news/business/companies/novartis_ag/index.html?in\

line=nyt-org) trial results. “Any positive results from

clinical trials will be amazingly hopeful.â€

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.â€

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 — 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_

(http://health.nytimes.com/health/guides/symptoms/hyperactivity/overview.html?in\

line=nyt-classifier) , 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_ (http://www.fraxa.org/) , a

nonprofit organization dedicated to financing fragile X research. “This may

be

the key to solving the mystery of autism and other developmental disorders.â€

Geraldine Dawson, chief science officer at _Autism Speaks_

(http://www.autismspeaks.org/) , 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_

(http://health.nytimes.com/health/guides/disease/down-syndrome/overview.html?inl\

ine=nyt-classi

fier) — 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 Dr. Fishman refused to divulge many details. Dr. Luca

Santarelli, head of neuroscience at _Roche_

(http://topics.nytimes.com/top/news/business/companies/roche-holding-ag/index.ht\

ml?inline=nyt-org) , 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_ (http://www.broadinstitute.org/psych/stanley) at the Broad Institute

at

_Harvard_

(http://topics.nytimes.com/top/reference/timestopics/organizations/h/harvard_uni\

versity/index.html?inline=nyt-org) and the _Massachusetts

Institute of Technology_

(http://topics.nytimes.com/top/reference/timestopics/organizations/m/massachuset\

ts_institute_of_technology/index.html?inline=nyt

-org) .

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.â€

An Unlikely Beginning

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

then a graduate student in _genetics_

(http://health.nytimes.com/health/guides/specialtopic/genetics/overview.html?inl\

ine=nyt-classifier) at _Michigan

State University_

(http://topics.nytimes.com/top/reference/timestopics/organizations/m/michigan_st\

ate_university/index.html?inline=nyt-org) , 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_

(http://topics.nytimes.com/top/reference/timestopics/organizations/e/emory_unive\

rsity/index.html?inline=nyt-org

) , 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_

(http://www.nytimes.com/info/alzheimers-disease/?inline=nyt-classifier) and

_Parkinson’s_

(http://health.nytimes.com/health/guides/disease/parkinsons-disease/overview.htm\

l?inline=n

yt-classifier) .

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 — 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_

(http://health.nytimes.com/health/guides/symptoms/seizures/overview.html?inline=\

nyt-classifier) .

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. _

(http://topics.nytimes.com/top/reference/timestopics/people/c/francis_s_collins/\

index

..html?inline=nyt-per) , director of the _National Institutes of Health,_

(http://www.nih.gov/) in discussing the science leading up to the trial. “

But it has not been easy.â€

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_

(http://health.nytimes.com/health/guides/surgery/c-section/overview.html?inline=\

nyt-classifi

er) , 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_

(http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/hos\

pitals/index.html?inline=nyt-classifier) 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 — both Harvard graduates with post-graduate

degrees — 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.â€

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.â€

She paused, looked at her mother and said: “You’ve got 10 years.â€