Advanced Parkinson's Symptoms Controlled by Gene Therapy

NEW YORK, June 21 -- Motor symptoms of advanced Parkinson's disease were significantly improved in a small investigational gene-therapy trial, according to investigators here.

The gene therapy approach aimed at calming excitatory pathways rather than preserving dopaminergic neurons, reported Michael G. Kaplitt, M.D., Ph.D., of Weill Cornell Medical College, and colleagues, in the June 23 issue of The Lancet.

In a phase I, proof-of-concept study, 12 patients with advanced Parkinson's had significant reductions of motor symptom scores on the Unified Parkinson's Disease Rating Scale (UPDRS) following gene therapy targeting the subthalamic nucleus.

The improvements in motor symptoms started at about three months after treatment and lasted for up to a year, the investigators reported. There was no evidence of significant adverse events either in the immediate post-therapy period or through one year.

The authors found that the therapy produced substantial improvements in the UPDRS motor ratings subscale in both the off and on states (P=0.0015). There were also significant improvements in motor symptoms in both the off and on states (19% improvement off P=0.0244, and 25% improvement on P=0.0182), continuing out to one year (24%, improvement off, P=0.0038 and 27% improvement on, P=0.0098).

Ten of the 12 patients had improvements in UPDRS off scores at one year: four improved between 0% and 20%, two between 20% and 40%, and four improved more than 40% in whole body off motor scores, with most of the benefit occurring in the limbs on the side of the body contralateral to the hemisphere of the brain that was treated.

There were no significant improvements in the activities-of-daily-living scores in either the off or on states at any time during the study, however. There were no significant changes in the UPDRS dyskinesia ratings, the amount of antiparkinsonian medication used per day, or in any of the neuropsychological tests, the authors reported.

The therapy involves injection unilaterally into the subthalamic nucleus of an adeno-associated virus modified to carry the GAD gene, which encodes for glutamic acid decarboxylase. This in turn catalyzes synthesis of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain.

In patients with Parkinson's disease, there is an increase in activity in the subthalamic nucleus caused largely by a reduction in GABAergic input from the globus pallidus, the authors wrote.

Reduction of excitatory activity in the subthalamic nucleus -- with either deep-brain stimulation, strategic surgical placement of lesions, or GABA infusion - has been shown clinically to alleviate signs of advanced Parkinson's. In animal models, gene therapy with GAD had provided clues that the therapy may improve brain function and reduce signs of the disease without toxic side effects, the authors noted.

"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," said Dr. Kaplitt. "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."

If the therapy is successful, it could reduce or obviate the need for deep-brain stimulation, which involves placement of in-dwelling hardware and electrical leads that could provide a path for infectious agents, Dr. Kaplitt and colleagues said.

The open label trial of the therapy involved 11 men and one woman. The mean age of the patients was 58.2 + 5.7 years, and each had a Hoehn and Yahr Parkinson's staging scale score of three or greater, and motor fluctuations with substantial off time.

The patients underwent clinical assessment both off and on medication at baseline, and months one, three, six and 12. The evaluations included UPDRS scores, scales of activities of daily living neuropsychological testing, and PET imaging with 18F-fluorodeoxyglucose.

All 12 patients had surgery, which involved infusion of the viral vector-GAD combination into one hemisphere of the brain under sterotactic vision with MRI guidance. The original protocol called for bilateral injections, but this was modified by federal regulators to only one hemisphere "because of the concern that unexpected toxic effects might produce a more devastating outcome if they happened bilaterally," the investigators noted.

FDG-PET scans showed that there was a substantial reduction in thalamic metabolism restricted to the treated hemisphere, and a correlation between clinical motor scores and brain metabolism in the supplementary motor area, providing further evidence of a treatment effect, the authors said.

"Kaplitt and colleagues have taken a provocative approach to the treatment of neurodegenerative disease, and should be congratulated for their circumspection in the description of the potential implications of their findings," wrote A. Jon Stoessl, M.D., of the Pacific Parkinson's Research Center at the University of British Columbia, in Vancouver, in accompanying editorial.