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A Gene Therapy For The Brain Technique aims to quiet Parkinson's By Jamie Talan STAFF WRITER August 19, 2003 Preparation for yesterday's pioneering surgery that delivered genes into the brain of a Port Washington man with Parkinson's disease began almost a year ago, when the Food and Drug Administration gave permission for the experimental procedure in up to a dozen patients. Scientists at the FDA and the National Institutes of Health had scrutinized such experimentation in rats, which was successful in reversing movement problems associated with Parkinson's. Research involving monkeys was recently completed and is still being analyzed. Yesterday, Nathan Klein, 55, became the first human recipient of gene therapy targeted directly at an adult brain disease, said Dr. Michael G. Kaplitt, a neurosurgeon at New York Weill Cornell Center who performed the operation. During the procedure, which he helped develop, Kaplitt infused billions of genes, packed in particles of a virus, into the target area of the brain. Weill Cornell doctors had prepared in collaboration with North Shore- Long Island Jewish Health System. The technique is being developed and tested by Neurologix, a New Jersey- based company started by Kaplitt's father, Martin, a cardiac surgeon who started the open heart surgery program at North Shore University Hospital. His son, the neurosurgeon, is a nonpaid consultant to the company and will not be involved in the patient follow-up or the analysis of the results. Parkinson's patients have long been willing to step up to the operating table for relief from the tremors, stiffness and rigidity that characterize the disease. Decades ago, surgeons began to make lesions in parts of the brain involved in the disease, which lessened symptoms. Fetal stem cell surgery was pioneered in Parkinson's patients. And in the past decade, stimulating electrodes placed in the brain's subthalamic nucleus have brought some relief to as many as 70 percent of patients who have opted for the surgical procedure. If it doesn't work, the electrodes can be removed. The New York doctors say the gene therapy procedure could be a more natural way to treat the disease in lieu of deep brain stimulation, which requires surgically implanted hardware and long-term maintenance. "Instead of silencing the subthalamic nucleus electrically, we are inserting a gene that has an inhibitory, or silencing, role," said Dr. David Eidelberg, a neurologist at North Shore-Long Island Jewish Health System in Manhasset. Eidelberg and Dr. Andrew Feigin are overseeing the Parkinson's patients recruited for the gene therapy study. The gene therapy technique was developed by Dr. Matthew During of the University of Auckland in New Zealand and the Long Island-born Kaplitt, director of stereotactic and functional neurosurgery at Weill Cornell. Fifteen years ago, Kaplitt, then a graduate student at Rockefeller University in Manhattan, began experimenting with different gene delivery techniques. He went on to medical school to become a neurosurgeon. Kaplitt completed a fellowship at the University of Toronto, where he learned surgical techniques for Parkinson's. In 1993, Kaplitt teamed up with During, who also was working on gene therapy techniques for brain diseases. Together they performed the animal studies that would lead them to their goal of treating humans. Parkinson's is a movement disorder caused by a progressive depletion of the brain chemical dopamine in an area of the brain called the substantia nigra. These dopamine-containing cells control movement. When 70 to 80 percent of these cells are destroyed, a person develops the first symptoms of disease: tremors, slowed movement, muscle rigidity and problems with balance. The main medication used in Parkinson's is L-dopa, which replaces dopamine in cells that are still functioning. But over time, the cell death is so massive that the effects of the medication disappear. Kaplitt says he has benefited from the knowledge gained from other Parkinson's techniques. The transplanted fetal stem cells, while promising, were like dopamine-producing factories on a runaway train, he said. Some patients who received the transplanted fetal cells did have relief from symptoms, but also had new ones due to the overproduction of dopamine. They experienced involuntary movements, which could not be reversed. The success with cutting certain areas of the diseased brain led scientists to the idea of deep brain stimulation, which would also quiet overactive regions. In this procedure, doctors place electrodes in the subthalamic nucleus, which sits on top of the substantia nigra. Many scientists have reported that the inhibitory brain chemical called GABA is reduced in the subthalamic nucleus - and that causes the overexcitement of the cells. This abnormal message leads to many of the movement problems in these patients. "When you lose dopamine, that is only the beginning," said Kaplitt. "Dopamine is like the key to the car. But if you hotwire the car, you don't need the key." The hotwiring, in this case, is a harmless virus filled with a gene called GAD (glutamic acid decarboxylase) that turns the excitatory brain chemical glutamate into the inhibitory brain chemical GABA. These genetically modified brain cells protect dopamine neurons from subsequent damage. The animal studies have shown that the gene therapy technique works. Kaplitt's Toronto mentor, Dr. Andres Lozano, once injected GABA itself directly into the subthalamic nucleus, which briefly quieted this area and improved the patient's symptoms while undergoing deep brain stimulation. But despite the mounds of safety data, "rats are not human," Kaplitt said. And the scientists have a built-in safety net, in case something unexpected happens once the genes are surgically infused into the brain. "If there is a problem, we may be able to go back in and lesion the area," Kaplitt said. Electrodes could also be placed into the subthalamic nucleus to gain control of the region. During yesterday's procedure, they infused 3.5 billion viral particles, each containing the GAD gene. Only a small portion of these genes will make it into the 100,000 or so cells in this region. The viral vector that delivers the gene into the cell is metabolized and disappears from the brain, Kaplitt said. While this is designed as a first-step safety study, Eidelberg will be taking brain scans of the region to see if the cells are doing what they are intended to do. As in the animal studies, it could take months to see an effect. No one is calling this a cure. "Most things in medicine we just treat really well," said Kaplitt. "We don't cure heart disease with a bypass. We are trying to take advantage of what we know works. By using gene therapy, we can get rid of the hardware and maybe make it work a little better. If so, this would be a major feat." As with any brain surgery, there are risks of hemorrhage or stroke as a result of passing leads through the brain to infuse the therapy. Although postoperative scans show hemorrhage in as many as 10 percent of cases, the majority of these are asymptomatic, but could still be cause for concern, Kaplitt said. Gene therapy holds great promise but has had serious problems in its development for human diseases. In 1999, Jesse Gelsinger, 18, died after a gene therapy procedure in a study at the University of Pennsylvania. He had a genetic disorder that left him unable to produce enzymes that remove ammonia from the body. Federal investigators have said they believe the adenovirus, or an inactivated cold virus, that was used to deliver the genes produced a fatal immune response in Gelsinger. More recently, two children in France developed a leukemia-like disease years after undergoing gene therapy to cure an immune disorder called "bubble boy disease." Kaplitt and During chose not to use the same gene-delivery agent used in earlier gene therapies, an adenovirus. Instead, they turned to a smaller virus called AAV, one that isn't able to replicate on its own and has not been associated with any human diseases, During said. 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