Fragile X study raises hopes for autism

Researchers eye key to restoring brain function

By Carey Goldberg, Globe Staff | June 26, 2007

Blocking a key brain chemical can reverse many of the symptoms of Fragile X Syndrome -- an inherited form of mental retardation often accompanied by autism -- in mice engineered to have the disease, an online scientific journal reported yesterday.

The findings raise the prospect that drugs with similar effects might someday help restore brain function in human children with the syndrome, and possibly with some forms of autism as well, said Susumu Tonegawa, the senior author of the paper in the online edition of the Proceedings of the National Academy of Sciences.

About 100,000 Americans have Fragile X.

Mental retardation has long been thought to be permanent. But recent research increasingly suggests that the brain might be more fixable than previously believed. Earlier this year, scientists from Scotland reported that dramatic recoveries could be achieved in mice with Rett Syndrome, another genetic disease related to autism.

Tonegawa's paper says "that some of the abnormalities with mental retardation syndromes and autism aren't necessarily cemented in stone," said Eric Klann, a professor at Center for Neural Sciences at New York University who was familiar with the paper but not involved with the research. "I think it gives some degree of hope."

The research focused on blocking an enzyme called PAK. Tonegawa's research used genetic manipulation instead of drugs, but he said that he believes drug and biotech companies are already developing compounds that block the same enzyme. His lab may seek access to such compounds that target other diseases, or ask a chemist to synthesize them, said Tonegawa, a neuroscientist at Picower Institute for Learning and Memory at the Massachusetts Institute of Technology .

There are currently several drugs in development as possible treatments for people with Fragile X Syndrome, said Katie Clapp, co founder of FRAXA Research Foundation, a Newburyport based nonprofit that helped fund the research. Her 18-year-old son has the syndrome, the most common known genetic cause of autism. None of the compounds has reached the point where she would want him to try them, she said, nor are they available.

"But talk to me in a couple of months," she said. "There are more drug targets coming out of research that we're funding, and some of it does suggest drugs that are already available. So sometimes I feel like I'm living a dream -- a really good one."

In people with Fragile X, the formation of neurons is abnormal, with "spines" -- the little nubs where the neurons connect to each other -- that are overabundant, spindly, and long. Clapp said they are "sort of like a thin, dangly . . . little wire when what you really want is a nice, thick, three-pronged, grounded thing." The thin spines tend to form weak connections.

In Tonegawa's lab, Mansuo Hayashi, then a post-doctoral fellow and now at Merck Research Laboratories, had already found that when PAK activity was genetically blocked, it hindered the formation of spines, leaving them shorter and fatter with connections that were unusually active.

In all, he said, it seemed that blocking PAK produced spines exactly the opposite from those produced in Fragile X Syndrome.

Hayashi proposed cross-breeding a mutant mouse whose PAK could be inactivated with a mouse engineered to have Fragile X Syndrome, in the hope that the two abnormalities would cancel each other .

At first, the idea seemed overly simplistic, Tonegawa said, "but to our great surprise, that's the way it turned out."

The cross-bred animals were also genetically manipulated so that the PAK-blocking would begin several weeks into the mouse's life, well into childhood in human terms. Nonetheless, the effects were striking, the researchers reported.

Normally, the Fragile X mice are hyperactive, as are many of the human children with the syndrome : They engage in repetitive motions, as is common in autism, and have learning deficits. Many of those symptoms were reduced or reversed when PAK's activity was blocked, Tonegawa said. Within the animals' brains, as well, the neurons and their connections came to look and act much more normal .

"It's reversing the architecture of brain connections," Clapp said. "That's exciting."

Carey Goldberg can be reached at goldberg@globe.com