The root cause of Down's syndrome is an extra copy of an entire chromosome. And so it may seem like any attempt to treat the resulting symptoms pharmacologically is an endeavor that has no beginning and no end.

But in the April 2007 issue of Nature Neuroscience, researchers from Stanford University show that in mice with a syndrome that mimics Down's, the blockage of a specific receptor and the resulting neural disinhibiton can have long-term positive effects on the animals' cognitive abilities.

"The idea is that too much inhibition can impair learning and memory circuits, and that is an underlying cause of mental retardation," senior author Craig Garner, a professor at Stanford, told BioWorld Today. Down's syndrome patients vary widely in their cognitive abilities, but their average IQ is in the range of 40-45. Garner believes that "if you could move the IQ 20 points, this could make a big impact not just on the individuals, but on their parents and caregivers."

In their paper, Garner and his team used the drug PTZ to treat so-called Ts65Dn mice, which have three copies of parts of mouse chromosome 16 and symptoms, including cognitive deficits, similar to those seen in people with Down's syndrome.

Animals that received PTZ, which decreases neural inhibition by inhibiting GABAA receptors, performed better on a learning task. Brain slices taken from PTZ-treated Ts65Dn mice animals also showed better long-term potentiation, a neural mechanism of learning and memory storage, in response to electrical stimulation. Both improvements persisted for at least a month after the animals stopped receiving the drug, suggesting that PTZ is able to remodel neural circuits.

PTZ has a long and colorful history. It has been in use for basically this, that and the other thing since the 1920s, as everything from a cardiac stimulant to an alternative to insulin shock treatment. One of its uses has been in geriatric populations to help with cognitive problems, but Garner said that those studies were not sufficiently well controlled to draw any firm conclusions, though the patients "generally seemed to do better."

Garner noted that his team's work has several important limitations. For one, it is not possible to cure an extra chromosome.

"All you can really do is treat the symptoms," he said. Perhaps even more importantly, it is impossible to predict what the effects of bumping up a person's IQ from 40 to 60 will be - especially given the fact that Down's syndrome individuals, as a group, tend to be an extremely cheerful lot to begin with.

"When you make them aware, that doesn't necessarily make them happy," Garner said. "One hopes that this would improve their quality of life, but that is, of course, very subjective."

Nevertheless, he said he is "working very diligently toward putting together a clinical trial." That includes working with several companies to get the drug tested for its toxicology properties, and discussions with several biotechs about possible clinical development of the drug. Because PTZ is so old, its composition-of-matter patent, if there ever was one, has long since expired. Stanford holds method-of-use patents.

Between the science, the medicine, and the business issues, Garner said that for now, the outlook for treating Down's syndrome one day is a carefully balanced one. "Yes, there is hope," he said. "But there needs to be caution and patience with the way forward."