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Gene Therapy for Parkinson's Nearing Reality

Safety study of gene treatment set to start in 12 patients

THURSDAY, Oct. 10, 2002 (HealthDayNews) -- A form of gene therapy can ease the movement problems of rats with Parkinson's disease, and scientists are now poised to bring the treatment to people with the debilitating condition.

Parkinson's disease is caused by the destruction of dopamine-producing neurons, but the illness has wide-reaching effects throughout the brain. Eventually, the balance between excitement and inhibition of neurons is thrown off kilter. As a result, the brain's motor centers are in a perpetual state of arrest.

The new approach, reported in tomorrow's issue of Science, in effect lets off brake that has locked up these motor centers. Ironically, the latest work hinges on the brain messenger molecule known as GABA, which is the main chemical that keeps neurons still.

Increasing the levels of GABA unlocks the activity of a brain center called the STN, which links dopamine neurons and the movement regions. In Parkinson's patients, loss of dopamine spurs the STN to tell the motor centers to freeze.

The result is a dramatic -- and often nearly complete -- reversal of the tremors, rigidity and other movement troubles associated with Parkinson's, says Matthew During, a brain disorders expert at the University of Auckland, New Zealand, and leader of the new research. "Every animal got better, but it varied from 20 percent to 80 percent recovery," says During, whose group has received approval from the U.S. Food and Drug Administration to study the therapy in people.

During's method mimics the effects of deep brain stimulation, a Parkinson's treatment in which doctors excite neurons in the STN. Dosing STN neurons with GABA tells them to be quiet, and in turn lets motor neurons get excited again.

Doctors can generate this effect for a few seconds by administering a drug to the area that triggers GABA receptors there. But that's not a practical long-term treatment, During says.

With gene therapy, however, GABA production can be increased permanently, and with no apparent side effects to the animals. STN neurons "now make their own GABA, but if there's too much being released they just shut down," he says.

Scientists have used gene therapy in animals to tinker with dopamine neurons and growth factors that protect those cells. However, those approaches have been prone to side effects. During, who helped perform the first gene therapy experiments with Parkinson's disease more than a decade ago, says the new technique is safer than previous attempts.

In addition, it uses an organism called an adeno-associated virus (AAV) to shuttle a gene, GAD, which promotes GABA production, into the brain. This virus is considered safer than the retroviruses deployed in the gene therapy trials for severe immune problems recently halted by regulators in the United States and France.

During, who founded the Newark, Del.-based biotech company Neurologix, is now organizing a safety study of the GAD therapy in 12 people with severe Parkinson's who no longer respond to other treatments.

The patients will receive low, medium and high doses of the gene treatment, and will undergo brain scans and neurologic and motor tests for a year. The study, set to begin in a matter of months, will be the first human trial of a gene therapy for Parkinson's disease.

Michal Stachowiak, a gene therapy researcher at the State University of New York at Buffalo, says the latest results seem promising. However, he believes it's still too soon to bring gene treatments into Parkinson's patients unless those therapies are better than non-genetic remedies already available, such as deep brain stimulation. "It's sophisticated molecular and cell biology, but in terms of clinical function I'm not sure that this is superior," he says.

Parkinson's disease affects between 1 million and 1.5 million Americans, causing movement disorders as well as cognitive and emotional problems. Drugs and other treatments can help control some of these symptoms, but there is no cure for the illness.

What To Do

To find out more about Parkinson's disease, try the Parkinson's Disease Foundation or the National Institute of Neurological Disorders and Stroke.

SOURCES: Matthew During, professor, University of Auckland, New Zealand; Michal Stachowiak, Ph.D., associate professor, anatomy and cell biology, State University of New York, Buffalo; Oct. 11, 2002, Science
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