29 October 2000

Gene Therapy Reverses Effects Of Parkinson's Disease

by Kate Melville

Researchers at Rush-Presbyterian-St. Luke's Medical Center, Chicago, and Lausanne, Switzerland, have successfully used gene therapy to reverse the anatomical, cellular changes that occur in the brains of primates with Parkinson's disease. The researchers also report success in preventing the disease from progressing and reversing functional deficits or symptoms associated with the disease in monkeys displaying early signs of Parkinson's disease.

Results of the research are published in the Oct. 27 issue of the journal Science.

Rush scientists used a special virus (lenti-GDNF), which was developed by colleagues in Switzerland to deliver the gene for glial-derived neurotrophic factor (GDNF) directly to the brain cells of monkeys.

GDNF is a nutrient that strengthens and protects brain cells that would normally die in this disease. GDNF also increases production of the chemical neurotransmitter dopamine, which sends signals in the brain that enable people to move smoothly and normally. The loss of dopamine in the brain causes the symptoms of Parkinson's disease.

"The lentiviral vector delivery system was effective in getting GDNF to the specific sites needed to rescue the cells and enhance the production of dopamine. By giving GDNF, we can stimulate dopamine production and prevent both the structural and functional consequences of cell degeneration that are characteristic of Parkinson's disease," said Jeffrey H. Kordower, PhD, the principal author of study. He is professor of neurological sciences and director of the Research Center for Brain Repair at Rush-Presbyterian-St. Luke's Medical Center in Chicago. Study collaborators at the Lausanne University Medical School are Patrick Aebischer, MD, PhD, and Nicole Déglon. PhD.

Two groups of monkeys were involved in the research. The first group was studied to determine if and how the lentivirus delivery system affected the anatomy of the aged brain cells. The second group was studied to identify whether the lentivirus treatment had any affect on the behavior or functional problems associated with Parkinson's disease.

The first group in the study involved eight, aged monkeys (approximately 25 years old) whose brains displayed specific cellular changes associated with early Parkinson's disease. In this stage of the disease, the brain cells remain intact but either stop making dopamine, or make less dopamine than normal. They received six injections of the lenti-GDNF into the brain.

Before treatment, the monkeys' brains were analyzed using positron emission tomography (PET). After three months of treatment, their brains were extensively analyzed using PET as well as neuroanatomical, neurochemical and molecular biological techniques. The results showed a dramatic increase in the production of dopamine, similar to levels of dopamine found in the brains of young monkeys.

The second group included 20 young monkeys with no symptoms of Parkinson's disease. To evaluate any changes on function or behavior during the course of the study, each monkey was trained to perform consistently on a hand-reach task requiring them to pick-up food treats out of recessed wells. They were also analyzed on a Parkinsonian clinical rating scale (CRS), an observational assessment of movement analogous to one used by neurologists to assess patients with Parkinson's disease. The CRS assessment and the hand-reach task training indicated that they did not have any symptoms of Parkinson's disease.

The monkeys then received the chemical MPTP, which has been shown to initiate a Parkinson's disease-like state in monkeys and humans. A week later they were tested again using the hand-reach test and the CRS. The monkeys exhibited great difficulty in performing the hand-reach task, and the CRS analysis also verified the presence of Parkinson's symptoms.

The animals were then injected with the lenti-GDNF. One week later, a three-month re-testing period was begun using the hand-reach task and the CRS. As a result of the lenti-GDNF treatment, performance on the hand-reach test improved to near normal, similar to how they performed prior to injection of MPTP. Scores on the clinical rating scale also improved significantly.

The monkeys in this second group also received a PET scan, and their brains were extensively analyzed. Results showed that the treatment completely prevented degeneration of the dopamine system: brain cells and their fibers were preserved, and increased levels of dopamine were produced.

As a control for the study to insure that it was not the injections themselves that resulted in improvements but rather the lenti-GDNF, half the monkeys in each group received injections of a control lentivirus, lenti-�Gal. The monkeys receiving the lenti-�Gal virus displayed robust expression of �Gal, indicating the effectiveness of the lentivirus delivery system. However, as expected, the delivery of the lenti-�Gal had no effect on the structure and anatomy of the brain cells and did not improve the impaired behavior of the Parkinsonian monkeys.

A third group of normal monkeys received lenti-GDNF and was allowed to survive for eight months. High levels of GDNF were found in these animals, demonstrating long-term gene expression using this delivery system.

"The study suggests a new approach to forestall disease progression in newly diagnosed Parkinson's disease patients by delivering potent trophic factors with effects that are long-term and non-toxic," Kordower noted.

He anticipates that clinical testing in humans of the lentiviral delivery system for GDNF will begin in Switzerland and the U.S. in less than five years following review in this country by the Food and Drug Administration.

The research was supported by grants from the U.S. Department of Defense; the Swiss National Science Foundation; and the Swiss National Program in Neurological Diseases.

Parkinson's is a slowly progressive disease that affects a small area of cells within the mid-brain known as the substantia nigra. Gradual degeneration of these cells causes a reduction in a vital chemical neurotransmitter, dopamine. The decrease in dopamine results in one or more of the classic signs of Parkinson's disease that includes: resting tremor on one side of the body; generalized slowness of movement; stiffness of limbs; and gait or balance problems. The cause of the disease is unknown. Both environmental and genetic causes of the disease have been postulated.

Parkinson's disease affects about 1.2 million patients in the United States and Canada. Although 15 percent of patients are diagnosed before age 50, it is generally considered a disease that targets older adults, affecting one of every 100 persons over the age of 60. While there is currently no cure for Parkinson's disease, progressive treatments allow many patients to maintain a high level of function throughout their lifetimes. It is not a fatal illness.