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In a study published today in the journal Science, scientists from the University of Auckland and Weill Cornell Medical College report on the effectiveness of a new gene therapy approach to Parkinson's disease, and the potential for this therapy to affect the overall progression of the disease itself. Based on this study and other data, the U.S. Food and Drug Administration (FDA) has given its approval to begin testing this therapy in a small Phase I clinical trial. This will be the first time in the world that gene therapy will be used in patients with Parkinson's disease.

The Science publication is authored by lead investigator, Dr. Matthew J. During, Professor of Molecular Medicine at the University of Auckland, first author Dr. Jia Luo, and co-investigator Dr. Michael G. Kaplitt, Director of Stereotactic and Functional Neurosurgery and Assistant Professor at Weill Cornell Medical College. Dr. During and Dr. Kaplitt are also co-principal investigators on the upcoming clinical trial of this therapy.

"We are using gene therapy to 're-set' a specific group of cells that have become overactive in an affected part of the brain, causing the impaired movement and other symptoms associated with Parkinson's disease," said Dr. During. "We are very encouraged that in addition to the effect this therapy has on quieting symptoms, we present evidence that suggests it may arrest or delay disease progression."

People with Parkinson's disease have a profound loss of a specific group of nerve cells deep in the brain which make dopamine, a signaling molecule. The loss of dopamine leads to a disturbance in the brain's network activity controlling movement. In the center of this network is a region called the subthalamic nucleus (STN), which in Parkinson's disease is extremely overactive, and if silenced leads to a dramatic reduction in the symptoms.

Targeting the overactive cells, researchers inserted the "GAD" gene into a viral vector (adeno-associated virus or AAV) to allow it to be efficiently delivered into the affected region of the brain. GAD is responsible for making a small molecule called GABA, which is released by nerve cells to inhibit, or dampen activity. After this gene therapy is introduced, the overactive cells are "re-set," and brain network activity controlling movement returns towards more normal function. In 1994, Dr. Kaplitt and Dr. During were the first to demonstrate that AAV could be a safe and effective vehicle for gene therapy in the brain. Since that time, AAV has been used safely in a variety of clinical gene therapy trials, and the virus has never been associated with any human disease.

Although medical therapy is usually effective for most symptoms of Parkinson's, over time many patients become resistant to treatment or develop disabling side effects. "Current surgical therapies for such patients attempt to interrupt this network abnormality by destroying overactive brain areas or placing DBS (deep brain stimulation) electrodes to quiet these areas. Both of these treatments, however, have certain limitations and side effects," said Dr. Kaplitt. "Our approach is based on a similar rationale, but we use gene therapy to adjust the chemical signaling of these brain areas to a more normal setting. This exploits the best parts of current therapy but makes it more powerful, less invasive, and potentially safer."

The Science paper reports on testing of this theory using a combination of techniques to measure brain function in rodents that were made Parkinsonian. Five tests were conducted. These tests showed the GAD gene was present and producing GABA as anticipated. Several behavior tests were also conducted in the rodents to show they had retained more normal function and did not develop further signs of Parkinson's as did the control rats. In addition to work in rodents, primate studies demonstrated that the therapy was safe, and there were no toxicities associated with the treatment.

Based upon the recent FDA approval, the first Phase I trial of this treatment is anticipated to begin within the next few months. Selected patients will undergo surgical gene therapy at NewYork-Presbyterian Hospital/Weill Medical College of Cornell University by Dr. Kaplitt. These patients will be recruited and followed by Drs. David Eidelberg and Andrew Feigin at the North Shore Hospital Long Island Jewish Movement Disorder Clinic. The initial trial will be limited to 12 patients with severe Parkinson's disease, of at least five years duration, for whom current therapies are no longer effective.

"The Science report and our team's translation of this approach to treatment of human disease represent the culmination of over a decade of research in this area," said Dr. During. "Our primary objective has been to stress patient safety above all else, and the NIH (National Institutes of Health) and FDA have helped us design a clinical intervention which has exciting efficacy potential and attempts to minimize in any way possible risks of adverse events to patients in the study. It is our hope that with this approach, our trial will help demonstrate that gene therapy in the brain can be both safe and effective."

Other contributing authors include Helen Fitzsimons, David S. Zuzga, and Yuhong Liu from the Functional Genomics and Translational Neuroscience Laboratory, Department of Molecular Medicine and Pathology, University of Auckland, New Zealand, and Michael L. Oshinsky from the CNS Gene Therapy Center, Jefferson Medical College, Philadelphia, PA.