Scientists at Jefferson Medical College have used gene therapy to reverse the progression of Parkinson's disease in rats.
They have found that by adding a gene for an enzyme, they were able to reprogram brain circuitry and halt the deterioration of dopamine producing brain cells, one of the key problems in the disease.
According to the authors, in Parkinson's, a portion of the brain called the subthalamic nucleus is overactive. These cells produce glutamate, an excitatory neurotransmitter into the substantia nigra, which is important for the coordination of movement and where the brain chemical dopamine is made.
The researchers 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 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.
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 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. Furthermore, the changes appear to be permament.
The group already has approval from the Food and Drug Administration
for a clinical trial, which will be the first gene therapy protocol for
© 2002, Jefferson Medical College