OREGON: New path on Parkinson's - GDNF - (glial cell line-derived neurotrophic factor)

The Oregonian
09/24/03
ANDY DWORKIN

Oregon's Greg Moore is the first U.S. resident to undergo a daring and intriguing surgery aimed at halting the
crippling progression of Parkinson's disease.

Shortly before Labor Day, the 56-year-old checked into OHSU Hospital, where doctors planted two catheters deep in his
brain.

They anchored the tubes to his skull, to keep them from moving, and attached the catheters' other ends to pumps sewn
beneath the skin of his abdomen.

Two weeks ago, the doctors used a syringe to fill the pumps either with a placebo or with a protein called GDNF, for
glial cell line-derived neurotrophic factor, which helps nerve cells grow strong.

"It's a little bit like a hormone that's produced by one cell, that's very important to the functioning of other nerve
cells," said Dr. Jay Nutt, director of The Parkinson Center of Oregon at OHSU. He compared it to the way testosterone
fuels the growth of men's beards.

If Moore got the GDNF -- neither he nor his doctors will know until the study ends -- the pump will start bathing his
brain with the protein. Doctors hope that shower will dramatically decrease the frustrating bouts of being unable to
control body movements that are a hallmark of Parkinson's.

"It's about the first thing that's come along in a long time that offers the potential -- and I underscore potential --
to change the course of the disease," Moore said.

Nearly 200 years after it was first described, doctors can't stop the slow but inevitable decline caused by
Parkinson's. The disease is caused by the death of brain cells that make dopamine, a chemical that helps spread nerve
messages.

The result is bouts of trembling that can alternate with periods in which sufferers' limbs grow stiff and immobile.
Patients often move slowly and unsteadily, and they can have trouble with basic tasks such as walking, talking, feeding
themselves or tying their shoes.

The disease, which normally strikes people 60 and older, is one of the most common U.S. neurological diseases. At least
500,000 U.S. residents have Parkinson's, including Muhammad Ali, Michael J. Fox and former U.S. Attorney General Janet
Reno.

Science provided Parkinson's patients significant relief in 1970, when a drug called levodopa hit the market. It gets
processed into dopamine in the brain, which eases Parkinson's symptoms but doesn't stop cell death. Some surgeries
similarly aim to relieve symptoms by destroying small parts of the brain or implanting an electrode to stimulate them.

The search continues for a way to actually slow, if not stop, the cell death that causes Parkinson's. Several ideas
have inspired hope in recent years that such a breakthrough might be around the corner.

One idea involves transplanting new dopamine-making cells into the brain. Scientists have experimented with a variety
of these cells, including cells harvested from patients' adrenal glands and stem cells taken from embryos.

Experiments with stem cells and transplants into lab animals looked promising. Initial transplants into humans showed
dramatic improvements, including reductions of as much as 60 percent in some disease symptoms.

But hope faded somewhat when doctors ran a double-blind study, implanting fetal tissue in some patients' brains and
doing "sham surgery" on others by just drilling holes in the skull. Patients who got stem cells did show some
improvement, but mostly in people 60 and younger, rare for Parkinson's. And several transplant patients suffered
significant side effects.

While research into cell transplants continues, attention has shifted to fighting Parkinson's with "neuroprotective
agents." These are chemicals designed to protect nerve cells from dying and, perhaps, to heal injured cells. They
include GDNF, the agent in OHSU's trial.

First isolated in 1993, GDNF is naturally made in the brain to protect and strengthen dopamine neurons, said Shana
Behrstock, a University of Wisconsin researcher who studies the protein. Tests in animals showed that GDNF also seems
to affect nerve cells that process movement and sensory information, Nutt said.

Intrigued, scientists tested GDNF on animals whose dopamine-making cells were injured with a toxin, to mimic
Parkinson's. The protein seemed to protect the brain when given before the toxin, Nutt said. It also helped when given
after the toxin, raising the possibility that GDNF might save failing neurons from death.

Such work looked promising even when tried on primates, humans' closest relatives. So Nutt and colleagues led a study
in which they put GDNF into patients' ventricles -- the network of openings that channels spinal fluid through the
brain.

The treatment did not help. Nutt and others think GDNF might be too big to move from the ventricles through many layers
of brain tissue to reach the areas affected by Parkinson's.

But that experience helped lead Moore to the operating room.

Directing treatment to need If GDNF couldn't move through much brain tissue, doctors figured, perhaps they needed to
put it directly where they wanted it. By using brain imaging and very precise measurements, surgeons are able to put
catheters in a region called the putamen. This is not where the dopamine cells are dying, doctors said, but a
neighboring area where those dying cells had spread signals to neurons that control movement.

In March, doctors from England and Wisconsin reported on five patients who had this surgery, with dramatic results. All
five had been immobile roughly 20 percent of their waking hours before surgery. But six months after, none had still
periods. After a year, standardized tests showed a nearly 50 percent improvement in their ability to control motions
and perform tasks.

"The results that they've had there are very encouraging," said Dr. Matthew Brodsky, another OHSU Parkinson's expert.

But doctors know too well that improvement in such tests can be because of patients' positive mental outlook, also
known as the placebo effect. That, combined with the small number of patients, tempered hope for the new treatment. It
also spurred OHSU and several other hospitals worldwide to embark on the new trial.

Nutt said about 30 people will be treated in this study, including four patients already chosen at OHSU.

"These tend to be patients with moderate-to-advanced Parkinson's disease," Brodsky said.

Doctors will track the patients for six months after surgery, measuring their health with standardized tests. They also
will use brain scans to track dopamine production and use, which could indicate whether GDNF only prevents new cells
from injury or actually helps revive weak, poorly-working cells.

Benefits or placebo effect Although 30 patients is not many, the fact that some will get a placebo should help doctors
discern whether any benefits are attributable to patient expectations. Nutt added that studying 30 patients is only
enough to show large benefits, not modest ones. But that is fine, he said, because the surgery is so dramatic that
doctors would pursue it only for a big improvement.

If the study reveals big benefits, doctors probably will expand the tests. With more success, GDNF could be used in
early-stage Parkinson's patients to stem the disease's progression. Doctors also might explore new ways to get GDNF
into the brain, Nutt said, including using genetically engineered viruses or stem cells that would create biological
protein factories in the brain.

Similar techniques might help people with other diseases that kill brain cells, including Alzheimer's disease and Lou
Gehrig's disease, Brodsky said. However, those diseases affect more diffuse brain areas than Parkinson's, which could
be a big hurdle in treating them with GDNF.

Moore, who has had Parkinson's for 14 years, said he has participated in a number of drug studies. Medicines let him
work and be fairly active until about two years ago, when his leg tremors and other symptoms became more frequent and
unpredictable. Then he retired from his job with a telecommunications company and started "looking at the degenerative
nature of this" disease.

Wanting to act decisively, he volunteered for the GDNF study in November 2002. Moore said he wasn't deterred by the
idea of having his brain operated on. In fact, the surgery and recovery were surprisingly quick. Moore checked into the
hospital early on Aug. 27 and went home at 5 p.m. the next day.

"I was feeling pretty lousy when I got out of the operating room," he said, but felt better a few days later. The main
difference now is the two pumps that "stick out through my shirt," Moore said. "But that's an awfully small price to
pay."

"I'm not sure I'll get the real joy juice in this thing, because . . . half the people will get the placebo," he said.
Still, "I think there's a lot of excitement in the community. I know I'm excited." Andy Dworkin: 503-221-8239;
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SOURCE: The Oregonian, OR
http://tinyurl.com/ohcy

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