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Gene therapy may offer an effective way to combat Parkinson's Disease

Parkinson's Disease is a debilitating brain disorder in which, over a period of years, you loose the ability to control muscular movement. Arms begin to shake, facial muscles to twitch. Parkinson's disease is named after Dr. James Parkinson, who first described the disorder as a shaking palsy in 1817. About one million Americans are afflicted with Parkinson's Disease.

What causes Parkinson's? Researcher Arvid Carlsson discovered a critical clue in the 1950s -- that a brain chemical called dopamine is unusually common in the midbrain where muscular movement is controlled. The dopamine allows the cells there to communicate with one another and so control movement (Carlsson was awarded the Nobel Prize for this discovery last month). In Parkinson's individuals, the midbrain cells that produce dopamine begin to die. We don't know why. Without adequate dopamine, the muscle-controlling cells of the midbrain cannot do their job properly, and body movements become more difficult to control.

To treat Parkinson's, we administer a chemical called L-dopa, which is converted by the brain into dopamine This increases the dopamine available to the brain, and so alleviates many of the symptoms of Parkinson's.

Unfortunately, administering L-dopa only treats the symptoms of the disease. It does not address the basic problem, which is that dopamine-producing nerve cells are dying in the midbrain. Slowly, progressively, more cells die. L-dopa can only slow the process of what Parkinson called "the saddest of diseases."

To stop the disease in its tracks, we would like to halt the progressive dying of midbrain dopamine-producing cells that is the true cause of the disease. But we don't know how.

There is, however, another possible approach. If we could induce the healthy nerve cells that remain to sprout additional nerve fibers, the added cell mass would allow the healthy cells to make more dopamine. In this way, we might be able to replace the production capacity that has been lost.

There is a brain chemical that might do the job. It has a jaw-breaker of a name: glial cell-derived neurotropic factor. Lets call it GDNF. In tissue culture, GDNF is a potent stimulator of growth in midbrain dopamine-producing cells, causing treated cells to sprout many new projections. While GDNF might not stop the slow process of cell death characteristic of Parkinson's, maybe accelerated growth of healthy cells would compensate.

Last week a team of U.S. and Swiss researchers reported that they had succeeded in using gene therapy to introduce the GDNF gene into the midbrain of Rhesus monkeys. These monkeys were chosen because their midbrain muscular coordination regions are organized much like human ones.

The success of gene therapy depends critically on using an effective delivery vehicle. Viruses like adenoviruses have proven too dangerous -- our immune systems sometimes react to them violently. Tiny parvoviruses such as AAV are nearly invisible to the human immune system, and have been used recently to cure hemophilia in four individuals by transferring anticlotting factor IX. We cannot use AAV to treat Parkinson's, however, because parvoviruses do not enter nerve cells.

To carry the GDNF gene into midbrain cells, these researchers used instead a slow-growing virus related to the AIDS virus. This virus is harmless, readily infects nerve cells, and does not produce a strong immune response.

The researchers injected the GDNF-carrying virus directly into the midbrains of rhesus monkeys with chemically-induced Parkinson's (specific chemicals were used to damage the monkey's midbrain dopamine-producing cells). Virus carrying another unrelated gene was introduced into other control monkeys.

In the control monkeys, there was no effect. But in GDNF-treated monkeys, dopamine levels in the midbrain soon began to rise. In one to two months, the Parkinson's symptoms began to decrease. In short, the treatment worked.

There is still a critical hurdle that must be overcome before GDNF gene therapy can be attempted in humans. Some of the GDNF-treated monkeys produced excessive dopamine. Too much dopamine drives the brain into psychosis. Indeed, antipsychotic drugs work precisely because they counteract the effects of dopamine. For GDNF gene therapy to be safe, it will be necessary to devise a delivery system that will allow the GDNF gene to be switched on and off. This would allow patients to adjust their dopamine levels to avoid the side effects of too much or too little dopamine.

Just such a control system has already been used successfully to control the level of red blood cell production in gene therapy treatment of anemic rhesus monkeys. Taking a pill once a month flicks on the gene for a burst of red blood cell production. No one knows if this will work for GDNF in humans. But the possibility is exciting, and work continues furiously.

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