Gene Therapy for Parkinson's Advances

Brain surgery to insert genetic cargo improves movement for some

Using brain surgery to insert replacement genes, doctors can alleviate some movement problems in people with Parkinson’s disease. While not all of the gene therapy recipients in a new study improved, the group on average registered tangible gains after getting a gene that revs up production of a much-needed neurotransmitter, researchers report in an upcoming issue ofLancet Neurology.

Notably, none of the patients had significant side effects attributable to the therapy.

“The pendulum on gene therapy has really swung back and forth,” says study coauthor Matthew During, a physician and neuroscientist at Ohio State University in Columbus. “It was enormously hyped at first.” But the death of a patient in Philadelphia in 1999 and the appearance of leukemia in children in France getting gene therapy for an immune disorder—leading to a temporary suspension of trials in 2003—stalled the research. “The field languished for a while,” During says.

But he and his colleagues have continued to pursue the technology, using a disabled, nonpathogenic virus as the delivery vehicle for potentially useful genes. To treat Parkinson’s disease, the team has targeted a troublesome part of the brain where signaling gets obstructed in patients with the neurological disorder.

In the new study, the researchers randomly assigned 16 patients with advanced Parkinson’s to undergo an operation to install gene replacements; 21 similar patients got sham surgery and received no genes. Neither group was told which operation they were getting.

Doctors measured each patient’s physical movement before surgery, using a standard scoring formula for Parkinson’s patients. Six months after surgery, the patients given gene therapy showed an average improvement of 23.1 percent in their scores, compared with a 12.7 percent improvement among the sham surgery group. The formula measures problems such as freezing up, tremors and uncontrolled movements.

“This experiment was extremely well constructed and well designed,” says Michael Hutchinson, a neurologist at New York University who wasn’t involved in the trial. “This seems to be a positive effect, but not a clinically big effect.” Even so, he says, it clears the way for a larger study with more patients and possibly larger doses of the gene therapy.

The therapy zeroes in on a brain region called the subthalamic nucleus. While its normal role is poorly understood, this region becomes overactive in Parkinson’s patients, blocking signals that regulate muscle movement. Parkinson’s patients lack a brain-signaling molecule called dopamine, and that shortage results in the loss of another neurotransmitter called GABA in the subthalamic nucleus, triggering overactivity there.

The experimental therapy delivers a gene encoding an enzyme that boosts GABA production in the subthalamic nucleus. When it works, the gene therapy calms this region and smooths the flow of messages in the brain by allowing signals governing muscle movement to be shuttled through the nearby thalamus, Hutchinson says.

Another Parkinson’s treatment, called deep brain stimulation, uses an implanted electrode to quiet the subthalamic nucleus (SN: 1/31/09, p. 13).

The placebo effect seen in the people getting sham surgery is a curiosity not uncommon in Parkinson’s treatment, During says. Just getting the operation, in which “burr holes” are drilled into both sides of the skull under light sedation, stimulates optimism in the patient and results in a rise in dopamine production, alleviating some symptoms, he surmises.

During, who teamed with study coauthor and neurosurgeon Michael Kaplitt of Weill Cornell Medical College in New York City and others on the study, says a larger trial is planned. Meanwhile, people who got the sham surgery in this trial are now being offered the gene therapy.

Some patients from an earlier safety trial of this gene therapy are still showing sustained improvement; one is now seven years post-surgery. “It appears the clinical benefit persists,” says During, and that the transferred genes continue to help calm the overactive subthalamic nucleus. He and Kaplitt are cofounders of Neurologix, a biotechnology company based in Fort Lee, N.J., that financed this trial and makes portions of NLX-P101, the gene therapy medication.