Down 'cure' might be within reach

By Carey Goldberg, Globe Staff, 1/27/2004

A decade ago, any researcher who dared to suggest that Down syndrome could one day be "cured" was heading straight for the scientific fringe. Mainstream consensus went: Down syndrome, the leading genetic cause of mental retardation, was too complex a problem even to approach.

Now, although that goal remains beyond the horizon, a growing number of reputable researchers at universities such as Stanford and Columbia say they can foresee a time when they'll be able to break the link between Down syndrome and retardation.

Armed with an array of new tools -- from genome mapping and stem cells to genetically engineered mice and a deepening understanding of Alzheimer's disease -- they are trying to pinpoint just how the extra chromosome of Down syndrome leads to retardation and a host of other problems.

Once they figure that out, the thinking goes, perhaps they can someday help people with Down Syndrome gain some IQ points, or even develop normal intelligence. There is a precedent: Certain rare genetic metabolic diseases once meant certain retardation. Now, those babies can grow up mentally normal, thanks to diagnosis as newborns, pills and diet restrictions.

"The whole research scene has changed dramatically" since the extra chromosome, Chromosome 21, was mapped in 2000, said Suzanne Armstrong, spokeswoman for the National Down Syndrome Society.

"We realize that any potential treatments resulting from research at the genetic level are years away," she said, "but we're very hopeful."

More than 350,000 Americans have Down syndrome and the moderate or mild retardation that generally goes along with it. They are at higher risk for heart defects, childhood leukemia and other physical problems, too. They also tend to have a distinctive look -- short stature, small nose, a relatively flat face.

The life expectancy for people with Down syndrome has doubled in the last two decades or so, from 25 to 49 years; and the sweeping movement to raise children at home instead of in institutions has greatly improved the quality of those longer lives, parents and advocates say.

Sheila Cannon, coordinator for the Down syndrome center at Children's Hospital in Pittsburgh, said the progress on health and quality-of-life issues since her daughter, Kerry, was born 17 years ago has already been stunning: Back then, she was told, "Down Syndrome is what it is."

Now, it seems, that may not always be true. Prevention of mental retardation "may not happen within the next few years, and it may not even be helpful to my daughter, but it probably would be helpful to the generations that follow," she said. "That's how I look at it."

Getting there, advocates and researchers say, will require much more of a financial commitment from the federal government.

In recent years, federal funding for Down syndrome research has averaged about $10 million a year; the National Down Syndrome Society is now pushing for twice that sum. By comparison, Alzheimer's disease, which affects more than 4 million people, got $600 million from the National Institutes of Health alone in 2002.

But some of that river of Alzheimer's money is trickling over to Down syndrome research because of an intriguing connection: The brains of virtually all middle-aged people with Down syndrome show telltale signs of Alzheimer's disease, and one of the genes on Chromosome 21 is linked to production of beta-amyloid, a protein that accumulates in abnormal form in Alzheimer's brains.

The beta-amyloid connection raises an exciting prospect, said Dr. Michael Shelanski, codirector of the Taub Institute for Research on Alzheimer's disease at Columbia University:

It could be, he said, that a child with Down syndrome becomes retarded simply because "the child is developing with a flood of beta-amyloid, so they don't learn very well, they don't make synapses very well."

"We're beginning to study this in the mouse," he said, and eventually, perhaps, drugs that will be developed to sop up extra beta-amyloid in the brains of Alzheimer's patients could also be used to reduce retardation in children.

Human research is beginning as well. In a 2002 article in the journal The Lancet, researchers took two sets of post-mortem fetuses, one with Down syndrome and one without, and compared the gene activity of their neural stem cells. They found that certain genes that help brain cells develop and communicate were disrupted only in the Down syndrome fetuses. A Lancet commentary noted that those genes could turn out to be targets for drug and gene therapy in humans.

But that will take years to determine. In the meantime, a few clinical trials have begun to test existing drugs to enhance brain function in people with Down syndrome, largely on the premise that whatever shows promise improving learning and memory with Alzheimer's disease might work in Down syndrome as well.

Pfizer, which makes an Alzheimer's drug called Aricept, is testing it in dozens of people with Down syndrome around the country, checking for any noticeable improvement in memory, attention, language and more.

Results of previous studies of Aricept have tended to be modest, however, said Dr. Ira Lott, director of pediatric neurology at the University of California at Irvine. "The problem with that whole class of medication is that it's temporary," he said. "It's like whipping a tired horse -- the horse runs faster and then poops out."

He and colleagues are now working on a study using high-potency antioxidants -- such as vitamins E and C -- for people with Down syndrome. Already, the vitamins have shown some promise in improving learning and memory in Alzheimer's patients, he said.

Researchers tend to have an easier time imagining an antiretardation treatment that begins at birth -- or even before -- than one given in adulthood. But an adult treatment is not impossible, said Dr. William C. Mobley, director of a new center for research on Down syndrome at Stanford University. The effects of the extra chromosome "may or may not be reversible," he said. "We just don't know."

Years ago, a scientist stating that the retardation of Down syndrome could be prevented was "a voice in the wilderness," said Dr. Leonard E. Maroun, a professor emeritus of microbiology and immunology at the Southern Illinois University School of Medicine.

That is changing a bit, said Maroun, who has worked for years on the role that interferon, a virus-fighting protein used to treat some cancers, may play in Down syndrome. He has patented the idea of anti-interferon therapy and is developing an anti-interferon drug that he plans to sell through his Beverly-based start-up, Meiogen Biotechnology.

"The general public's image of Down syndrome is one of hopelessness," Maroun said. But, "I'm virtually certain we've got something that will really help. Maybe I'm wrong, but certainly there are ideas out there that make it plausible that we could help these kids, and could encourage scientists to get into this area."

Carey Goldberg can be reached at