First gene therapy clinical trial for Parkinson's disease improves patients' motor skills with no major side effects

In what could be a breakthrough in treating Parkinson's disease, researchers at NewYork-Presbyterian Hospital/Weill Cornell Medical Center improved the motor function of 12 patients over the course of one year by injecting a harmless gene-bearing virus into their brains.

The research, which marks the first phase 1 clinical trial using gene therapy to battle the progressive neurodegenerative illness, is published in the June 23 issue of The Lancet.

"These exciting results need to be validated in a larger trial, but we believe this is a milestone -- not only for the treatment of Parkinson's disease, but for the use of gene-based therapies against neurological conditions generally," said lead researcher Michael Kaplitt, the Victor and Tara Menezes Clinical Scholar in Neurological Surgery at Weill Cornell Medical College and director of Movement Disorders Surgery at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

"Viruses exist in nature mainly to transfer their own genes to the host cell," he explained. "So, we modify the AAV (adeno-associated virus) in such a way that the only gene it carries is the one we want to deliver to the therapeutic site."

In this case, the "gene of interest" is the glutamic acid decarboxylase (GAD) gene. "GAD makes a chemical called GABA, a major inhibitory neurotransmitter in the brain that helps 'quiet' excessive neuronal firing," said Matthew During, professor of molecular biology and cancer genetics at Ohio State University, the senior author of the study, who worked on this research while at Weill Cornell.

"In Parkinson's disease, not only do patients lose many dopamine-producing brain cells, but they also develop substantial reductions in the activity and amount of GABA in their brains. This causes a dysfunction in brain circuitry responsible for coordinating movement," During explains.

Thus, the researchers inserted the GABA-producing gene GAD back into an area of the brain called the subthalamic nucleus, a key regulatory center within this motor circuit, via the AAV.

"We saw no adverse events related to the treatment, no immunological changes or infections over the year of the study, no imaging evidence of toxicity whatsoever," Kaplitt said.

Three months, as well as one year, after treatment, the patients as a group showed a 25 percent to 30 percent improvement in motor function when they had been off their medications for 12 hours (the off state), and up to 65 percent improvement in some patients while they were on medication.

"That was really surprising and heartening, because traditional Parkinson's surgeries improve patients in the off state but not as frequently in the on-medication state," said Kaplitt, noting that the next step is a larger, more definitive efficacy-centered study. "We've now shown that the genetic modification of the patient's own brain cells can be done safely, and it appears to have enough effectiveness in this case to justify further exploration -- potentially opening up gene therapy for a host of brain disorders," he said.

About 1.5 million Americans have Parkinson's disease, which is characterized by a steady loss in brain cells producing the neurotransmitter dopamine, which alters the function of brain networks controlling motor function. Medications, as well as surgery, can treat some of the symptoms, but there is no cure.

This work was funded by Neurologix of Fort Lee, N.J., which is developing the AAV-GAD agent. Kaplitt and During are co-founders of the company and remain consultants. Additionally, Kaplitt's father, Dr. Martin Kaplitt, is chairman of the board of Neurologix and, as such, has stock ownership and receives salary.

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