Repair for mental impairment?

By completely reversing four types of mental impairment in mice, scientists are overturning the long-entrenched notion that our mental capacity is hardwired and immutable.

So striking were the animal results that scientists are beginning drug trials on people with genetic disorders associated with mental retardation and autism. Several of the drugs are approved for other uses, which should speed up the testing process.

Until recently, the thought of reversing mental retardation was the stuff of science-fiction stories such as the 1966 novel Flowers for Algernon.

"Most of us were convinced the development of the brain was disorganized and there was nothing you could do about it," said Alcino Silva, a neurobiologist at the University of California, Los Angeles. "It's a wholesale paradigm shift."

What he and others are discovering is that in many cases, learning problems stem from molecular-level imbalances, ones that drugs might correct.

In all these experiments, researchers used mice bred to suffer versions of genetic diseases that, in humans, can lead to mental retardation or autism.

"A pattern is starting to emerge," said Cambridge University neuroscientist Petrus de Vries. "We're beginning to understand the pathways that underlie a lot of learning in normal people."

De Vries, who is in charge of one of the human drug trials, cautioned that there was no telling at this early stage how it could turn out. "It may help or it may not," he said. "It may help some and not others."

The drugs might also have harmful side effects, and the trials will need to establish whether the benefits outweigh the risks.

The disease Silva studies, tuberous sclerosis complex (TSC), is associated with learning disorders, epilepsy and autism. Mice with TSC show similar symptoms that Silva was able to reverse using nothing more complicated than rapamycin, the organ-rejection drug.

The journal Nature Medicine published his work last month.

Despite the obscure names, these genetic disorders are surprisingly common. TSC affects about one in 6,000 people, Silva said, and about half are autistic. It stems from a defect on one of two possible genes, which leads to excess activity in the brain. The molecular machinery necessary for learning and memory is out of balance, he said, because of overactivity of a protein called a kinase.

Rapamycin acts on the kinase at the root of the disorder, he said.

"That machinery is inappropriately activated in TSC mice," he said. He suspects that TSC allows humans and mice to learn things they should ignore. "Instead of learning the right things, the mutant mice are learning a lot of stuff that won't help them in the maze."

The maze he refers to is really a tank of water with a small submerged platform the animals must find to escape. It's a standard test for learning and memory in mice.

"They are enormously motivated to find the platform," said Silva, since mice hate swimming. At first they rely on trial and error, but once trained, most normal mice will remember where the platform is and swim directly to it. TSC mice take a lot longer to learn this, perhaps being mislead by all the irrelevant information they learn.

But rapamycin changed that. "After three days of treatment, the TSC mice learned as quickly as the healthy mice," Silva said

The drug was already being used in trials of TSC patients in England, but only to test its efficacy against kidney and lung lesions, also associated with the disorder. Cambridge's de Vries, who is running those trials, said that until recently, most scientists hadn't expected the drug to work on cognitive problems because those had been thought to result from growths in the brain.

"We proposed there might be a molecular cause underlying the cognitive deficits," he said. But that was just a hypothesis until Silva repaired the deficits in his mice. De Vries said he met Silva for the first time in January, and the two began collaborating, with Silva concentrating on the mice and de Vries on the humans.

De Vries said he was monitoring his subjects for cognitive improvement and planned to disclose the results later in the summer.

Silva got equally surprising results using common statins on mice with a genetic disorder called neurofibromatosis (NF1). It's associated with mild learning and memory problems and tumors called neurofibromas, which can be disfiguring.

The disorder affects about one in 3,000 people, said Ype Elgersma, a neuroscientist at Erasmus University Medical Center in Rotterdam, Netherlands.

The genetic defect behind the disease leads to hyperactivity of a protein called RAS, Elgersma said. To function normally, RAS needs a small fat molecule that is a precursor to cholesterol, and Silva reasoned that by lowering this cholesterol precursor, statins might suppress the overactive RAS and restore the chemical balance needed for normal learning.

"In mice it works almost instantly," Elgersma said. "You give them statins and the brain starts to work in the normal range within days."

Because the drugs are known to be relatively safe, Elgersma has moved ahead with a clinical trial involving 60 NF1 patients ages 8 to 17.

Setting the stage for that work was research on fragile X syndrome, a genetic condition associated with learning problems such as mental retardation, attention deficit, unstable mood and autistic behaviors.

Again, these symptoms seem to stem from a chemical imbalance. People with fragile X make too many proteins in their brains, said Mark Bear, a neuroscientist at the Massachusetts Institute of Technology who has studied the condition for more than a decade. These excess proteins then overstimulate another protein called mGluR.

Last year, he and colleagues showed they could reverse the mental deficits in fragile X mice by altering the gene associated with mGluR.

"The question is, if you can correct this with genetic engineering, could you also correct it with a drug that would block some of the receptors?" Bear said.

At the University of Pennsylvania, a group led by Thomas A. Jongens has used the antianxiety drug fenobam to reverse a version of the disease in fruit flies.

"I think it's miraculous, and I don't use that word lightly," MIT's Bear said of the sudden, recent progress against fragile X syndrome.

Human trials of fenobam are under way at the University of California, Davis, and at Chicago's Rush University Medical Center.

At Stanford University, Craig Garner has found drugs that, in mice, reverse the learning deficits associated with Down syndrome. "They would bring the brain completely back online - like magical drugs," he said.

Unfortunately Garner's drugs are not approved for other uses, so they must go through the often lengthy approval process. The first human trials start in the fall, he said, but he's worried about the lack of funding.

There's more at stake than a few genetic diseases, said Cambridge's de Vries. These discoveries could give clues to treating much more common brain disorders, he said.

"A decade ago, most of the studies on mental health and neurocognition focused on diseases like ADHD, schizophrenia, autism and depression," he said. But scientists still don't understand the causes of most of these.

"In recent years, people have realized that specific genetic disorders such as fragile X and TSC may help us learn some of the answers to those big questions we couldn't answer before."

Disorder   Some Effects   Drugs Tested

Tuberous sclerosis   Autism, epilepsy, learning problems   Rapamycin

complex      (organ rejection)

Neurofibromatosis   Mild learning/memory problems,    Statins

skin tumors   (for cholesterol)

Fragile X syndrome   Learning problems, attention deficit,   Fenobam

unstable mood, autism   (for anxiety)

Down syndrome   Learning disabilities, Alzheimer's,   GABA antagonists

heart problems   (unapproved)

SOURCE: Researcher interviews

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