Fw: [ Trisomy10q ] Research in Genetic Disorders

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[ Trisomy10q ] Research in Genetic Disorders

>

> This article was in the Philadelphia Inquirer this morning. It may be

> something to keep in the back of our minds for the future....

>

> 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. "

>

>

http://www.philly.com/philly/hp/news_update/20080706_Repair_for_mental_impairmen\

t_.html

>

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