Encouraging signs are emerging of the first gene therapy trial for Parkinson's disease, researchers report in the June issue 23 Lancet . Although their study was only designed to test the safety of a gene in the brain cast of 12 patients, the researchers found that the patients have improved slightly on a scale for measuring engine capacity.
Parkinson's disease affecting 1.5 million Americans, occurs when the brain loses neurons dopamine. This loss disrupts the balance of neurotransmitters that control movement, resulting in tremors, stiffness, poor balance, and other problems. Patients can take a called levodopa, which is converted in the brain to dopamine, but it causes side effects and often stop working over the long term.
Alternatively, a team led by Michael Kaplitt and Matthew During of the Weill Medical College of Cornell University in New York want to add a gene called glutamic acid decarboxylase (GAD) to cells in the subthalamic nucleus, is hyperactive in Parkinson's patients. The gene encodes the enzyme that makes gamma-aminobutyric acid (GABA), a neurotransmitter which inhibits the firing of neurons. Their idea is that if they can get the crank GABA cells, it will calm activity in the subthalamic nucleus and other parts of the brain. It was five years ago, the group reported in Science This strategy seemed to work in rats with Parkinson-like disease.
Now these researchers tested their idea in 11 men and one woman with advanced Parkinson's disease. Working with others in New York, New Zealand and Neurologix, a company in Fort Lee, New Jersey, and during that Kaplitt founded the first team harnessed the GAD gene in a harmless virus, called adeno-associated virus (AAV), for transporting the gene in cells. They then infused a solution containing the viral vector through a catheter in the subthalamic nucleus of the 12 patients, who took about 1.5 hours. As a precaution, patients were given the drug in one side of the brain.
The researchers saw no side effects related to treatment reassuring news because AAV caused immune reactions in other gene therapy trials. And 3 months after treatment, patients began to improve a test of motor function called Parkinson Disease Rating Scale (UPDRS Unified). 12 patients showed an average improvement of 25% in the UPDRS after 1 year, with five improvement from 40% to 65%. Gains were mainly on the side of the body opposite to the side of the brain that has been processed. Brain imaging of metabolic activity also showed changes only on the treated side.
Although the improvement was "modest," said Durant, it is "highly encouraging from our point of view." The majority of patients are still doing better until 4 years after treatment, said Durant, now at Ohio State University in Columbus.
"These data are very promising," says Martha Bohn, a neurobiologist at Northwestern University in Chicago. Bohn said the placebo effect are "notoriously high" in Parkinson's studies, but the fact that patients have improved mainly on the treated side suggests that the inserted gene was the reason. But Ole Isacson of Harvard is skeptical, noting that there have been no published studies show that the therapy works in non-human primates. The improved motor function could result from an effect "drive" that patients have improved in tests over time, he suggested.
In the group plans to launch a larger trial later this year. Two other companies are also conducting trials Parkinson's disease gene therapy using different genes.
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