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Fragile promise

Parents push scientists to cure son's disease

Andy Tranfaglia's parents cannot wait for the usual slow march of science. So they nudge it along. They plant seed money. They keep scientists up past midnight brainstorming. They helped a researcher obtain human fetal tissue. They have even begun contracting out specific experiments that they want done.

Andy, 15, of West Newbury was born with Fragile X syndrome, an inherited form of mental retardation that also can include life-threatening seizures, autism and more. Soon after he was diagnosed, his Harvard-educated parents, Katie Clapp and Dr. Mike Tranfaglia, created a small research foundation called FRAXA to find a cure.

Now, after a decade of effort, they say the best lead yet has emerged, a theory explaining how the lack of one brain protein gives rise to the disease. The research is to be published this month by a Massachusetts Institute of Technology scientist, Mark Bear.

That work -- and FRAXA's ''huge influence" on it -- could yield drugs to alleviate or even eliminate some symptoms of Fragile X within five years, Bear said; without FRAXA's push, scientists might have done basic research for another 25 years.

Call it the ''Christopher Reeve Effect."

Foundations created by desperate family members or patients have been channeling money into biomedical research for decades. But Reeve, the paralyzed actor, does much more than that for spinal cord research. He has drawn attention also for diving into the science and demanding that researchers focus not just on deciphering nature's ways but on the potential for helping patients.

More quietly, noncelebrities also have been learning how to work the scientific research system toward their own ends.

A new book, ''His Brother's Keeper," chronicles how, from 1999 on, Jamie Heywood, an entrepreneur from a Newton family, metamorphosed into an amateur genetic engineer and biotechnology businessman in a driven effort to save his brother, Stephen, from Lou Gehrig's disease.

Such direct intervention by laypeople has become more possible because of advances in the science itself, said Dr. Oswald Steward, a prominent neuroscientist who chairs the scientific advisory committee of the Christopher Reeve Paralysis Foundation and also advises FRAXA.

Scientists have developed a clearer understanding of the genetic and molecular mechanisms of diseases from Fragile X to Parkinson's and Huntington's, he said, and now ''one can rationally trace a course from a basic discovery to clinical application in a reasonable time frame."

Andy's parents do contribute money to research: FRAXA raises and distributes a little more than a million dollars a year.

But they do much more.

They try to speed up information-sharing between researchers, unwilling to wait the two years it usually takes for journal publication, said Tranfaglia, a psychopharmacologist.

They try to induce scientists to override the demands of ego and develop other scientists' discoveries.

They sponsor research conferences.

And they do not hesitate to use their moral authority as parents of an affected child to encourage good behavior: ''Say one big hotshot wants to ask another hotshot for a research tool," said Clapp, a computer scientist. ''They might do it in front of me, so it's harder to say no."

FRAXA's enthusiasm for Bear's theory began, Clapp said, when Bear stopped by the foundation's booth at a major neuroscience conference in 2000 and let drop that he had the mechanism of Fragile X ''figured out," and it was ''really neat because compounds exist that can treat it." Then he walked away -- only to be chased down by Tranfaglia for more details.

Since then, FRAXA has worked to push the theory toward reality -- funding other researchers to look into it, enlisting a Columbia University scientist-friend, Robert Bauchwitz, to test it in mice, and helping to get animal trials of a promising drug underway.

Bear's theory, coauthored with scientists Kimberly Huber and Stephen Warren, is to be published in this month's ''Trends in Neurosciences." It goes something like this: It is already known that the Fragile X mutation blocks a critical protein. That protein normally dampens signals from a brain-chemical receptor called MGluR. So, without the protein, some MGluR's become overactive. That triggers a process that weakens connections between cells, impairing brain development.

If the theory is right, a drug that ratchets down some overactive MGluRs could treat the syndrome.

The idea that MGluRs are central to Fragile X fits with many of the disease's symptoms, Bear said. For example, the receptors are implicated in epilepsy, and Fragile X often involves seizures; they are involved in pain perception, and Fragile X can bring skin hypersensitivity; and they play a role in fear memories, and Fragile X often brings anxiety. There are a half-dozen more such seeming links.

Other Fragile X researchers are pursuing other avenues, including the possibility of gene therapy. But the Bear theory has particular appeal because major drug companies have been working to develop MGluR-blockers for years.

The trouble is, the drug companies are interested in the blockers to combat extremely widespread problems like anxiety or pain. Testing them for Fragile X, which affects only about 100,000 Americans, is not so appealing.

During a meeting with Fragile X researchers, Bear said, drug company scientists were ''super-sympathetic" but also said ''there's no way these drugs could be used for a Fragile X trial because, if there were a hiccup in those trials, it could jeopardize the larger market."

So, Bear, who is cofounder of a biotech firm called Sention, is putting his company where his theory is.

In yet another step beyond basic research, he has enlisted the company, in collaboration with FRAXA, to do the preliminary safety testing in cells and animals that is needed before MGluR-blocking drugs can be brought to clinical trials in humans with Fragile X. He is now trying to raise the money for it.

If an mGluR-blocker had already been approved for some other use, and, Tranfaglia said, ''if I had the stuff in my hands, we'd have a treatment. That's how close we are."

Tranfaglia's enthusiasm for the drugs stems in part from the fruits of an old friendship. He and Clapp asked Dr. Robert Bauchwitz, a neuroscientist at Columbia -- and a friend of theirs since freshman year at Harvard -- to test an mGluR-blocker in mice.

Bauchwitz worked with genetically engineered mice that have something close to Fragile X. In particular, the mice have violent and often fatal seizures. When he tried an mGluR-blocker called MPEP in them, the seizures stopped.

Now, Bauchwitz is working on a line of neural stem cells taken from a human Fragile X fetus that had been aborted to see whether the drug works in human brain cells. FRAXA helped connect him with the mother, he said, making the work possible.

In egging on everyone from good old friends to Nobel prize winners like Columbia neurobiologist Eric Kandel, Katie Clapp said she was partly inspired by the story behind the 1992 movie, ''Lorenzo's Oil."

Young Lorenzo's parents, Augusto and Michaela Odone, refused to accept the conventional medical wisdom that he would soon die of a rare genetic disease. Like Andy's parents, they pushed researchers and delved into the science.

The Odones' work continues now as ''The Myelin Project," in hopes of restoring function to Lorenzo, who, at 26, remains almost totally paralyzed and unable to speak.

But his mother, Michaela, who cared for him constantly, died of cancer in 2000. Her death underscores the urgency of FRAXA's work, Clapp said.

''You can't leave your son helpless like that," she said. ''We can't leave them helpless, that's part of the motivation behind all this. They have to die before us or be OK."

Carey Goldberg can be reached at goldberg@globe.com.

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