The first-ever phase 1 clinical trial using gene therapy to battle Parkinson’s disease is completed by a team led by physician-scientists at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
The study of 11 men and one woman with the progressive neurodegenerative illness found that the procedure – in which surgeons inject a harmless gene-bearing virus into the brain – was both safe and resulted in improved motor function for Parkinson’s patients over the course of one year.
The findings are 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,” says lead researcher Dr. Michael Kaplitt, associate professor of neurological surgery and 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.
Dr. Kaplitt has devoted much of his academic research career to the development of effective gene therapy techniques against Parkinson’s disease and other neurological disorders. In fact, 13 years ago, he and Dr. Matthew During pioneered a now widely used gene-delivery technique for the brain using an altered, harmless form of adeno-associated virus (AAV). In 2003, Dr. Kaplitt performed the world’s first gene therapy surgery for Parkinson’s, conducted at NewYork Presbyterian/Weill Cornell.
“Viruses exist in nature mainly to transfer their own genes to the host cell,” he explains. “So, we modify the AAV 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,” explains Dr. During, the senior author of the current study, who worked on this research while at Weill Cornell. Dr. During is now professor of molecular biology and cancer genetics at Ohio State University.
“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,” Dr. During explains.
The researchers’ bold idea: to insert the GABA-producing gene GAD back into an area of the brain called the subthalamic nucleus, a key regulatory center within this motor circuit.
“Our hope was that with a single operation to this single site, we could boost GABA production and thereby normalize the function of the entire circuit,” Dr. Kaplitt says. “Not only would this alter the chemical balance in the subthalamic nucleus; it should also provide GABA to other parts of the network that weren’t getting enough of the neurotransmitter.”
“We believe that this breakthrough trial has implications that go far beyond Parkinson’s research,” Dr. Kaplitt adds. “It’s taken us nearly two decades of hard work to get here, but the success of this trial lays the foundation for the use of gene therapy against neurological diseases generally. 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.”