Gene-Therapy Trial Offers Parkinson's Patients New Hope

Experimental treatment safely improved symptoms for six months, researchers say.

March 17, 2011— -- Walter Liskiewicz, an oral surgeon in Jackson, Mich., was 44 when he lost control of his body to Parkinson's disease. Fading signals from nerves dying deep inside his brain left his hands rigid and trembling and quickly forced him into early retirement. He found solace in music, writing and producing smooth jazz under the name Waldino. But within 10 years, he could barely move.

"Up to 70 percent of the time, I couldn't do anything," Liskiewicz, now 60, said. "I would sit in a chair."

Parkinson's disease disrupts a complex brain circuit that controls movement, making voluntary actions nearly impossible to initiate and involuntary ones impossible to control. Drugs that boost the effects of dopamine -- the neurotransmitter released by the degenerating neurons -- can help reduce the symptoms. The effects, however, gradually wear off and the side effects can become equally debilitating.

But the promising results of a gene-therapy trial have offered new hope to people with Parkinson's disease. The controversial approach uses virus particles to infuse new genes into a patient's own cells.

"This opens up the field of genetic medicine and brings us dramatically closer to it being a reality than ever before," said Dr. Michael Kaplitt, associate professor of neurological surgery at Weill Cornell Medical College in New York City and senior author of a report on the trial's results published in the Lancet Neurology.

Parkinson's disease affects roughly 500,000 people in the United States, making it the second-most common neurodegenerative disease after Alzheimer's. Drugs are the first line of treatment, followed by deep-brain stimulation, a procedure that implants electrodes deep into the brain to "hotwire" the damaged circuit.

Liskiewicz came across the clinical trial online one night.

"I asked my doctor about it and he said he had just applied to be one of the trial sites," Liskiewicz said. "I said, 'Make me No. 1 one on your list.'"

The goal of the therapy is to provide patients' cells with the blueprints to make proteins that have a therapeutic effect. In this case, the blueprint encoded an enzyme called GAD that would act like a chemical form of deep-brain stimulation, avoiding the need for electrodes, wires and battery packs.

"This procedure promised to provide the same things without all the hardware, and that was appealing," Liskiewicz said.

Promising New Option?

"Part of the reason we do research is to continue to offer patients new options," Weill Cornell's Kaplitt said.

Compared to deep-brain stimulation, gene therapy involves less hardware, less maintenance and fewer procedures, making it more cost effective and limiting the risk of infection, Kaplitt said.

But the experimental treatment comes with risks. The death of Jesse Gelsinger, 18, who joined a clinical trial for a rare liver disease in 1999 cast a shadow on gene therapy in the United States. The approach has the potential to provoke an immune response (the effect implicated in Gelsinger's death), cause unwanted changes in surrounding normal cells and irreversibly change the patient's DNA in ways that could potentially lead to cancer.

The results of a small phase 1 trial of GAD gene therapy in Parkinson's disease published in 2007 suggested the experimental treatment was safe. But to assess its effectiveness, the phase 2 trial was designed such that both the patients and the researchers were unaware who would get the therapy. This meant half the patients would have catheters tunneled into their brains only to receive the injectable equivalent of a sugar pill, a chance Liskiewicz was willing to take.

"It was just the promise of a better life," he said. "I just had faith in it, I guess."

Two months after the surgery, Liskiewicz knew he had received the treatment.

"I don't know why, I just did," Liskiewicz said. "I noticed small improvements. I could tell they weren't coincidental."

His wife, Constance Smith, noticed them too.

"Most of the time Walter looked angry or frustrated," Smith said, describing the Parkinsonian mask that prevents patients from expressing their emotions. "I missed the smile, the warmth that his expressions conveyed. After the surgery I noticed that he could smile."

Liskiewicz said he's "light years better" than a year ago before the trial. He still takes drugs but at half the previous dose, and says they work even better. Now he spends less than 5 percent of his time in his chair.

"I'm mobile. It's a great feeling."

Better Than Deep-Brian Stimulation?

According to the results of the trial, patients who received gene therapy had a 23.1 percent improvement in their motor score in six months of follow-up compared with a 12.7 percent improvement in patients who received a sham surgery and placebo; a difference that was statistically significant.

"This is not a cure," his wife said. "But it has dialed his disease back 10 years."

But some experts argue that deep-brain stimulation is still more effective.

"The extent of improvement arguably appears to be less than that documented for DBS [deep-brain stimulation]," said Dr. William Weiner, chief of neurology and director of the University of Maryland's Parkinson's Disease and Movement Disorders Center, adding that "new does not mean better."

Weiner said future studies should put gene therapy head-to-head with deep-brain stimulation rather than compare it to placebo.

Dr. Michael Okun, medical director of the National Parkinson Foundation, agreed, adding that a longer followup is needed to assess delayed benefits risks.

"This is an important study particularly in terms of safety," Okun said. "It opens the door to the hope for better symptomatic therapies in [Parkinson's disease], though patients should clearly understand their limitations, and that these are not neuroprotective therapies."

Liskiewicz is glad to have more functional time to work on his music and enjoy life with he wife and their two children. He hopes the trial offers new hope to people with Parkinson's disease.

"I hope it shows them that they're working on things that can actually work," he said. "They're in the pipeline.

"There's going to be a lot of things coming out in the near future that can improve their quality of life and well being."