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By Sean Henahan, Access Excellence

ROCHESTER, NY (2/6/97) Researchers are optimistic that promsing results obtained in gene therapy experiments involving rats with Parkinson's disease could someday be applied to the treatment of humans.

Scientists at the University of Rochester used gene therapy to provide protection to nerve cells in an animal's brain by boosting the production of a key protein messenger that staves off symptoms of Parkinson's disease.

"While this work is a long way from clinical application in humans, it is a prime example of the potential of in-vivo gene therapy in the brain," says graduate student Derek Choi-Lundberg. Using gene therapy to spur the brain to produce vital substances suggests a promising, less invasive route for a variety of neurological disorders, including Parkinson's.

Parkinson's disease targets a group of 200,000 to 400,000 dopamine-producing neurons in a section of the brain known as the substantia nigra, a tiny region smaller than a pea deep within the brain stem that serves as the brain's motor control center. These neurons produce dopamine, a neurotransmitter that's particularly important in the initiation and control of movement. In Parkinson's patients these neurons degenerate and eventually die; no one knows exactly why.

The Rochester team injected a modified version of the common cold virus, an adenovirus, directly into the brains of rats whose dopamine-producing neurons were exposed to a toxin, hydroxydopamine, that gradually kills the neurons. The virus, stripped of its ability to replicate, carried into cells the gene that encodes glial cell-derived neurotrophic factor, or GDNF, causing them to produce the substance directly. Over the next six weeks, neurons in untreated rats were three to four times more likely to die than neurons in the rats that received the GDNF gene.

Twenty years of neurological research has shown that neurons require a bath of proteins, called neurotrophic factors, to stay alive and healthy. About two years ago several research teams showed that one such factor, GDNF, can help keep alive the neurons that produce dopamine, the type of neuron that dies in patients with Parkinson's disease. Earlier this year, tests at the University of Kentucky College of Medicine showed that GDNF helped relieve Parkinson's symptoms in monkeys.

But getting GDNF into the brain is a problem because of its large size and short active life. In studies up to now, scientists have either injected GDNF protein directly into an animal's brain, or they have genetically engineered cells outside the body and then grafted them into the brain.

"Grafting cells into the brain, or repeating injections every few weeks or months, are fairly invasive procedures," says Martha Bohn, Ph.D., chief investigator and associate professor of neurobiology and anatomy at Rochester. "In our approach you simply inject a viral vector into a specific area of the brain once; you modify the area of the brain that is involved in the disease, and GDNF is secreted continuously in this area. That's what you need, since Parkinson's is a prolonged disease."

Adds Gene Redmond, director of the Neurotransplantation Program at Yale University: "There has been a great deal of work suggesting that GDNF might be useful in the brain; the critical limiting factor has been the lack of an appropriate long-lasting method of delivery. Packaging GDNF in a viral vector and inserting it directly into brain cells is quite ingenious."

Treatment for Parkinson's currently consists mainly of medication to boost the amount of dopamine in the brain, though a few patients opt for an experimental surgical procedure known as a pallidotomy. In most cases the disease progresses slowly over a period of years or decades, causing the tell-tale tremors, rigidity, and slow movement. Also underway are experimental clinical trials where surgeons transplant healthy fetal dopamine neurons into the brains of Parkinson's patients.

Scientists have conducted a few clinical trials involving neurotrophic factors. In two studies on patients with amyotrophic lateral sclerosis (Lou Gehrig's disease), therapy with a neurotrophic factor known as CNTF (ciliary neurotrophic factor) was not effective. Some patients even experienced side effects such as weight loss and coughing, which scientists believe were caused by the particular method of delivery.

"There's still interest in neurotrophic factors, but it seems clear that we must target their delivery specifically to the neurons that are dying," says Choi-Lundberg. "Gene therapy has the potential to do that."


Nearly one million people in the U.S. have Parkinson's disease. This is a mysterious disease with no known cause or cure. The cause of Parkinson's disease is currently thought to be a combination of environmental and genetic factors.

The symptoms of Parkinson's disease were first described by British physician Dr. James Parkinson in 1812. The first symptom is often an involuntary tremor. As the disease progresses, the muscles become stiff and the face loses all expression. Patients also develop difficulty walking and standing.

The first treatment breakthrough came with levadopa. The drug essentially replaces the lost dopamine in the brain. However, large doses are required, resulting in undesirable side effects, such as nausea, heart problems & dementia. The subsequent development of carbidopa, which is given in conjunction with levadopa, allows a smaller dose of levadopa to be used, resulting in fewer side effects.

Many patients respond well at first to this combination therapy, but after a couple years of treatment the effects may begin to wear off. At the same time, prolonged use of levadopa can have serious side effects including involuntary movements of the limbs and psychological disturbances.

A new treatment called seligiline has recently become available which has a completely different mechanism of action from levadopa. The drug is potent inhibitor of an enzyme called 'monoamine oxidase B' which breaks down dopamine. This means more dopamine can be preserved in the brain. The drug appears to have a neuroprotective effect and may delay the onset of Parkinson's symptoms.

The research appeared in the Feb. 6, 1997 issue of Science.

Related information on the Internet

AE: (11/96) Parkinson's Gene

Parkinson's Disease Foundation


AE (3/95) Gene for Rare Parkinson's variant

AE (1/95) Brain Therapy for Parkinson's

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