NY Weill Cornell patient receives first gene therapy for Parkinson's

By Timothy S. Paul

NEW YORK -- Surgeons at NewYork Weill Cornell Medical Center performed the world's first gene therapy for Parkinson's disease on a 55-year-old New York man Aug. 18. The historic surgery, which also marked the first-ever in vivo gene therapy in the brain for an adult neurological disease, was part of a phase I clinical trial approved by the Food and Drug Administration in October 2002.

The five-hour procedure was performed by Dr. Michael G. Kaplitt, director of stereotactic and functional neurosurgery at NewYork-Presbyterian Hospital and assistant professor of neurological surgery at Weill Cornell Medical College.

"Monday's surgery represents the realization of nearly 15 years of research in this area," said Kaplitt last week. "The goal of our gene therapy approach is to 're-set' a specific group of cells that have become overactive in an affected part of the brain, causing the impaired movements associated with Parkinson's disease. We hope that this trial, which is the first of its kind, will prove to be a safe treatment to allow gene therapy to move forward for Parkinson's disease and other brain disorders."

In the procedure, Kaplitt pinpoints the optimal location in the patient's brain using information from an advanced 3T MRI image, which is subsequently merged with a CT scan, using the latest computer imaging technology. Then, the final target is confirmed using fine electrical probes that identify the signature pattern of electrical activity of individual cells within the brain. During this process, the patient is awake and not medicated because medication and anesthesia can confuse the electrical information obtained. With the target obtained, the gene therapy agent (adeno-associated virus or AAV) is slowly delivered through a very fine catheter. After a 90-minute infusion, the catheter is removed, the skin closed and the patient sent to the recovery room.

AAV is the means by which the GAD (glutamic acid decarboxylase) gene enters the appropriate brain cells and begins production of a protein that produces GABA -- a molecule that is released by nerve cells to inhibit, or dampen, activity.

"Our intent, ultimately, is to normalize the chemical signaling of key affected brain areas in order to reduce the devastating effects of Parkinson's," said Kaplitt.

In 1994, Kaplitt was the lead author of a paper published in Nature Genetics, along with senior author Dr. Matthew During, professor of molecular medicine at the University of Auckland, which demonstrated, for the first time, that AAV could be a safe and effective vehicle for gene therapy in the brain. Last October, During was the lead author and Kaplitt the co-author of a paper in Science demonstrating the feasibility of the gene therapy approach used in last week's operation.

Since 1990, gene therapy has been used in clinical trials for a variety of conditions, including cystic fibrosis, cardiovascular disease, infectious diseases such as AIDS, and cancer. In the neurological arena, there has previously been one study of direct, or in-vivo, gene therapy for a rare pediatric neurogenetic disorder called Canavan's disease to try to protect cells that are dying. And there has been one study for Alzheimer's disease using transplanted cells which have been genetically modified in a dish to make a growth factor that might protect certain cells (so-called ex-vivo gene therapy). But the current study marks the first time that a gene has ever been put directly into an adult patient's own brain cells in an attempt to treat a neurological disease. Moreover, it is the first time that a gene has been put into the human brain not to protect cells, but with the intent of changing the very function of existing brain cells in order to alter overall brain function.