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About 6,000 U.S. babies are born with Down syndrome each year. Most attend school, aided by programs designed to help them deal with their disabilities. Now Roche Holding and Balance Therapeutics, taking advantage of a research renaissance in brain science, are testing drugs in human trials that may pave the way toward a new era. The goal: Improve the ability of these children to remember and learn.
The treatments aren’t a cure, and don’t address the underlying genetic problem. Instead, they aim to compensate for chemistry imbalances inherent in the condition by boosting the ability of nerve cells in the brain to communicate and form long-lasting connections, crucial for memory formation.
“Ten years ago if you told anyone there were going to be trials of drugs to improve cognitive symptoms of Down syndrome they would have laughed you out of town,” said Roger Reeves, a geneticist at Johns Hopkins University in Baltimore. The advances “in the just last five years are truly amazing.”
Down syndrome is among the most common genetic causes of intellectual disability, afflicting 250,000 Americans. It’s caused by having a third copy of chromosome 21. The main known risk factor is maternal age, with most cases occurring randomly in egg-cell maturation or sperm formation.
Besides mild to moderate cognitive impairment, the extra chromosome can cause problems that range from heart defects to hearing problems to intestinal disorders.
Michelle Schwab, of Holly Springs, N.C., whose 16-year-old son, Matthew, has the condition, says algebra is a difficult task for him because he can’t remember the steps needed to work out the problems. Spatial tasks, such as reading an analog clock, are also difficult, Schwab said.
Matthew is a freshman in public school, according to Schwab. A drug that would help him overcome those educational hurdles as he makes his way up through high school would “be tremendous,” she said.
“Because he functions so close to normally in every other area, it is frustrating to watch him struggle academically,” she said. “It would be wonderful if there were something that could enhance his cognitive ability, and just make things a little less difficult.”
Cognitive-enhancing drugs may have a significant impact, doctors say. An IQ boost of just 10 to 15 points could greatly increase the chance that someone with the syndrome would be able to live independently as an adult, said Brian Skotko, co- director of the Down syndrome program at Massachusetts General Hospital in Boston, who has a sister with the condition.
Children with the disorder benefit from federal laws that require schools to accommodate people with disabilities in regular classrooms as much as possible. Each change in the law “has improved the way students with Down syndrome are integrated into the classroom,” said Sara Weir, vice president of advocacy and affiliate relations at the National Down Syndrome Society.
Both Roche, based in Basel, Switzerland, and Balance Therapeutics, a closely held company in San Bruno, Calif., are testing drugs that counteract a chemical called GABA that depresses activity in brain cells. Lab studies suggest the extra chromosome may spur excess activity from the chemical, disrupting a crucial balance in the brain.
New technology developed in the last two decades has helped scientists dramatically increase their understanding of the sometimes subtle changes that occur within the brains of children with development disorders. They now see conditions such as Down syndrome and autism “as very specific pathologies that can be targeted with drugs,” said Omar Khwaja, a neurologist who leads Roche’s Down syndrome trials program.
A key step forward was the creation in the mid-1990s of a mouse with an extra chromosome that had many of the symptoms of Down syndrome, including memory problems, said Reeves, the Johns Hopkins researcher who has worked on the disorder since 1983. He and others showed that the mice had subtle deficits in the hippocampus, a region involved in learning and memory.
In 2004, Stanford University neurobiologist Craig Garner and a student of his at the time, Fabian Fernandez, realized scientists might be able to counteract the problem with drugs aimed at the same brain chemical targeted by the anti-anxiety medicine Valium and the sleeping pill Ambien. Those therapies calm the brain by boosting the brain chemical GABA; they also can produce memory problems.
A drug that did the opposite in key brain regions might enhance memory formation in people with Down syndrome by restoring a proper balance between inhibition and excitation of neurons, Garner said he realized.
Researchers did a test in mice using an old GABA-blocking drug called PTZ. After 17 days, the treatment normalized the rodents’ performance on mazes and certain object recognition and memory tasks for as long as two months, according to results published in 2007 in Nature Neuroscience.
“It was bloody amazing,” Garner said by telephone. “It was shocking how well it worked.”
Garner said he tried for years without success to get drug companies that had been pursuing GABA-blocking medicines for treating memory loss in the elderly to be interested in Down syndrome. In late 2009, he gave up and co-founded Balance Therapeutics with Lyndon Lien, a former Elan Corp. executive, and another scientist, Dan Wetmore.
Balance is now testing a GABA-blocking drug, BTD-001, on 90 adolescents and adults with Down syndrome in Australia, with results expected by early next year, said Lien, chief executive officer of the company.
The Stanford results and related research did, in fact, get the attention of Roche neurobiologist Maria-Clemencia Hernandez, who has been working on cognitive-boosting drugs targeting GABA since 2001, potentially for a variety of memory disorders. In 2008, she proposed to her superiors to test the medicines specifically in Down syndrome.
A study published in February 2013 in the Journal of Neuroscience showed that one of the Roche drugs restored memory function and increased brain-cell growth in mice with Down syndrome. A human efficacy trial, set to begin within weeks, will test a related Roche compound in 180 adolescents and young adults with Down syndrome.
The research carries some risks. Suppressing GABA too broadly could lead to side effects such as seizures. Roche’s drug, though, is targeted narrowly at areas of the brain involved in cognition.
An initial safety trial of Roche’s drug in adults with Down syndrome didn’t find any sign of seizures or related anxiety symptoms, said Stepan Kracala, a Roche spokesman, in an e-mail.
The condition has long been a research stepchild. The National Institutes of Health spent a $20 million on Down syndrome research in 2012, compared with $86 million for cystic fibrosis, which is less common. Now, though, with a more precise understanding of how the extra chromosome disturbs brain function, scientists are beginning to jump in.
“This was a condition that for many years was chalked up as one we could never do anything about,” said Skotko of Massachusetts General Hospital. “Now researchers are unlocking some of the mysteries of Down syndrome and for the first time we have drug companies that are investing their own dollars” in developing treatments.
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