Phila Inquirer Article on reversing mental impairment

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Posted on Sun, Jul. 6, 2008

Repair for mental impairment?

By Faye Flam

Inquirer Staff Writer

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 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, , 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. "

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Mental Impairments Under Study

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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Contact staff writer Faye Flam

at or fflam@....