NEW YORK CITY—After more than a decade of research and preparation, a team from the New York Weill Cornell Medical Center in New York City recently became the first to administer Parkinson’s disease gene therapy to a human patient. The five-hour procedure marked the start of a five-year phase I clinical trial that was approved by the FDA in October of last year.

The treatment was initially surgical, requiring a quarter-sized hole to be opened in the skull of the patient, a 55-year-old man with Parkinson’s disease. Recombinant adeno-associated virus vectors were then infused into the subthalamic nucleus. The vectors express two synthetic isoforms of the human enzyme glutamic acid decarboxylase, GAD65 and GAD67. These, in turn, synthesize gamma-amino butyric acid (GABA), the brain’s major inhibitory neurotransmitter.

“The goal,” said the trial’s primary investigator, Michael G. Kaplitt, MD, PhD, at a recent press conference, “is to restore the normal chemical balance of the subthalamic nucleus by enabling patients with Parkinson’s disease to synthesize their own GABA.” That is akin to “resetting” the brain portion that is overactive in Parkinson’s disease and thought to be responsible for many of the disease’s cardinal symptoms, remarked Dr. Kaplitt. He is an Assistant Professor of Neurological Surgery, Director of Stereotactic and Functional Neurosurgery, and Director of the Laboratory of Molecular Neurosurgery at Weill Cornell Medical College of Cornell University in New York City.

Before infusion of the gene therapy vectors, the subthalamic nucleus was located with MRI and CT. The target area for gene therapy within that region was then identified with electrical probes capable of detecting the pattern of electrical activity that characterizes Parkinson’s disease in individual brain cells.

WHY ADENOVIRUS?

The investigators chose a modified adenovirus as their gene therapy vector because, as Dr. Kaplitt put it, “viruses are nature’s gene delivery vehicles. They exist largely to transfer their own genetic material into cells.” In this case, however, the virus’ genetic material was replaced with synthetic GAD65 and GAD67; the only remnant of the original virus was its proteinaceous outer shell. The investigators decided to deliver synthetic GAD65 and GAD67 because the brain’s inhibitory neurons normally express both enzymes.

The phase I trial of Parkinson’s disease gene therapy will be limited to 12 patients who have had advanced Parkinson’s disease for at least five years. To be included in the trial, these patients must be unresponsive to, or unable to tolerate the side effects of, current Parkinson’s disease therapies and they must have significant balance problems.

After enrollment, the patients will undergo rigorous assessments at regular intervals. The assessments will include symptom evaluation, ratings of functional status based on the Unified Parkinson’s Disease Rating Scale, and neuropsychological tests of cognition, memory, and motor ability.

SAFETY FIRST

“We have multiple layers of safety data suggesting that [Parkinson’s disease gene therapy] is safe,” reported another principal investigator in the trial, Matthew J. During, MD, Professor of Molecular Medicine and Pathology at the University of Auckland in New Zealand.

The most recent of those data are from a 2002 study of gene therapy in parkinsonian rats, which displayed no posttherapeutic adverse effects. Moreover, the study linked gene therapy to improvement in parkinsonian behaviors and strong neuroprotection of nigral dopamine neurons.

The investigators produced similar findings eight years earlier when they safely injected their vector into the brains of parkinsonian rats. They used the vector to deliver lacZ, the structural gene that encodes ß-galactosidase, and human tyrosine hydroxylase, a key enzyme in the biosynthesis of dopamine and other catecholamines.

Injection of the vector that contained lacZ resulted in ß-galactosidase expression for up to three months while the tyrosine hydroxylase– containing vector produced immunoreactivity that was detectable in striatal neurons and glia for up to four months. The rats that received the latter vector also showed improvement in their parkinsonian behaviors.

In a 1998 study, a tyrosine hydroxylase or aromatic amino acid decarboxylase–containing vector was injected into the striatal cells of monkeys that had been exposed to a neurotoxin that caused Parkinson’s disease–like symptoms. Tyrosine hydroxylase produced detectable immunoreactivity in the striatal cells for up to about four and a half months, and several of the monkeys that received the gene showed elevated dopamine levels near injection tracts for up to two and a half months. Neither gene therapy caused significant toxicity.

CAUTIOUS OPTIMISM

While the main goal of the phase I trial is to confirm once and for all the safety of Parkinson’s disease gene therapy in humans, Dr. Kaplitt and colleagues also hope to gain insight into the treatment’s effectiveness. They speculate that, like deep brain stimulation, gene therapy will palliate Parkinson’s disease symptoms by inhibiting the activity of the subthalamic nucleus.

However, gene therapy may offer several advantages over deep brain stimulation, including the conversion of excitatory subthalamic nucleus projections into inhibitory projections, thus further reducing Parkinson’s disease symptoms. Additionally, gene therapy could be neuroprotective, and it would eliminate the need for the electrodes and batteries used in deep brain stimulation.

Like any unproven treatment, however, gene therapy could end up working poorly or failing completely in humans. It also presents the opportunity for severe brain damage if the surgeon is not careful when inserting the microthin infusion catheter or infuses the vectors too quickly.

“Forty-eight hours after the procedure, we are fairly pleased,” related Dr. Kaplitt. In fact, the first patient in the phase I trial was formally discharged at that time because he did not have a fever and showed no signs of brain damage or inflammation on MRI.

NR

—Timothy Begany

Suggested Reading
During MJ, Kaplitt MG, Stern MB, Eidelberg D. Subthalamic GAD gene transfer in Parkinson disease patients who are candidates for deep brain stimulation. Hum Gene Ther. 2001;12:1589-1591.
During MJ, Samulski RJ, Elsworth JD, et al. In vivo expression of therapeutic human genes for dopamine production in the caudates of MPTP-treated monkeys using an AAV vector. Gene Ther. 1998;5:820-827.
Luo J, Kaplitt MG, Fitzsimons HL, et al. Subthalamic GAD gene therapy in a Parkinson’s disease rat model. Science. 2002;298:425-429.

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