Gene Therapy Success In The Laboratory Buoys Hope For Parkinson's Disease

"It's not just inserting a replacement for a missing or mutated gene as a treatment for a genetic disorder," says Michael Oshinsky, Ph.D., research assistant professor of neurology at Jefferson Medical College of Thomas Jefferson University in Philadelphia and part of the team reporting its results October 11 in the journal Science. "This is more profound. We are actually changing the brain's circuitry as treatment for a disease."

According to Dr. Oshinsky and Jia Luo, M.D., research associate at Jefferson Medical College of Thomas Jefferson University, in Parkinson's, a portion of the brain called the subthalamic nucleus is overactive. These cells produce glutamate, an excitatory neurotransmitter, or chemical message carrier, into another region called the substantia nigra, which is important for the coordination of movement and where the brain chemical dopamine is made. Parkinson's is caused by the deterioration of dopamine-producing nerve cells.

The researchers - including scientists from Jefferson, the University of Auckland, New Zealand, and Cornell University - took their cues from work with deep brain stimulation, where brain cells in the subthalamic nucleus are stimulated at a high frequency as a treatment for late-stage Parkinson's. This treatment prevents overactivity in the substantia nigra.

The team, led by Matthew During, M.D., formerly of Jefferson Medical College of Thomas Jefferson University and now at the University of Auckland, decided that instead of turning off the neurons in the subthalamic nucleus, they would attempt to change the neurons from excitatory to inhibitory, which would then contain the inhibitory chemical messenger GABA.

The team used an adeno-associated virus to carry the gene for an enzyme, glutamic acid decarboxylase (GAD), into brain cells in rats that were made Parkinsonian. They saw a dramatic difference in the behavior and physiology of the Parkinsonian rats treated with the GAD-carrying virus compared to the Parkinsonian rats that did not receive the treatment.

Three weeks after the gene transfer, Dr. Luo made Parkinson's lesions on one side of the brains of rats that had the gene therapy. The researchers then performed various behavioral tests to see if the gene therapy could protect against the development of classic Parkinson's symptoms. One test showed that nearly 70 percent of the animals with Parkinson's lesions and the GAD gene therapy had no Parkinson's symptoms when they received chemicals that mimicked dopamine in the brain. Normally, animals with Parkinson's are hypersensitive to dopamine, and actually respond to it by running around in circles over and over. The test result was a "very strong behavioral measure showing this is a good treatment for Parkinson's," Dr. Oshinsky says.

The researchers also stimulated the rats' subthalamic nucleus and examined the resulting connection in the substantia nigra. They compared animals that had received the GAD gene therapy with those that had not had the gene therapy and normal rats. In the untreated Parkinsonian rats, more than 80 percent of cells showed excitatory responses. As few as 10 percent showed inhibitory responses.

But in the GAD-treated animals, they found practically the opposite. Nearly 80 percent of the neurons they recorded signals from showed inhibitory responses, whereas only about 17 percent showed excitatory responses. "It was a profound change in the connection between the subthalamic nucleus and the substantia nigra - that's where there was a phenotypic change in the neural connections," Dr. Oshinsky explains.

"By reprogramming it [the brain's circuitry], we actually could show that it was protecting dopamine neurons from dying off," Dr. During says. "The main advantage is that inhibitory input seems to protect the dopamine neurons."

"It's a classic excitatory connection in the brain and we converted it to an inhibitory connection," Dr. Oshinsky says. "It's nice to be able to show a real mechanism of action for a potential treatment of Parkinson's." He notes that the rats were tested as many as 10 months after receiving gene therapy; the change was permanent.

The group already has approval from the Food and Drug Administration for a clinical trial, which will be the first gene therapy protocol for Parkinson's disease.