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Gene therapy rejuvenates brain-damaged areas in monkeys with Parkinson's disease
By Bijal P. Trivedi

When monkeys with an induced form of Parkinson's are treated with the protein GDNF (glial cell line-derived neurotrophic factor), the dopamine neurons—whose destruction triggers the disease—are protected from dying. And motor skills that had been lost are regained after GDNF therapy.

In this new study, the researchers use a lentivirus to deliver the GDNF gene into the monkey's brains. Similar results have been seen in a rat model of Parkinson's disease, but the researchers used a different virus to carry GDNF.

"The new study is a big leap for Parkinson's research. It really isn't straightforward to go from using GDNF in the rat and then switch to the monkey and have the therapy work so well," says Martha Bohn, of Northwestern University Medical School, Chicago, who worked on the rat model of Parkinson's.

‘You can't just put a potent factor like GDNF in a human brain at high levels without knowing what it can do’

GDNF became an obvious drug candidate for Parkinson's, Alzheimer's and other neurodegenerative diseases when researchers discovered it could dramatically increase the survival and growth of many types of brain cells. The problem was getting it into the parts of the brain where it was needed. Now researchers are using gene therapy to deliver GDNF to protect and repair brain regions that are destroyed in Parkinson's disease.

Parkinson's is a particularly good candidate for gene therapy because the disease is primarily confined to dopamine neurons in two regions of the brain: the substantia nigra and the striatum. This makes targeting the right cells in the right regions a more focused task. These nerve cells produce and use the signaling molecule dopamine, and are particularly important for initiating and controlling movement. In people with Parkinson's, the nerve cells die and the amount of dopamine in the brain drops causing tremors, slow movements or rigidity.

The researchers' goal was to see whether GDNF could rescue dopamine neurons from death and reverse motor deficits caused by dopamine loss.

GDNF was tested in 25-year-old rhesus monkeys that showed a progressive loss of dopamine neurons similar to that seen in early stages of Parkinson's disease. The researchers encased the GDNF gene in a lentivirus and injected the virus into the substantia nigra and the striatum. The advantage to using this virus is that it does not trigger a strong immune response and it infects neuronal cells; a combination most viruses are unable to achieve.

After three months, PET scans measured dopamine activity in each monkey's brain. "Basically, we were able to dramatically increase the amount of dopamine produced. After treatment with the lentivirus GDNF, the PET scan showed dopamine function resembling that of an 8-to-12-year-old monkey," says Jeffrey H. Kordower of Rush-Presbyterian-St. Luke's Medical Center in Chicago, who led the study. The report is published in this week's issue of Science.

In another experiment Kordower and his colleagues tested whether GDNF therapy allowed monkeys to recover motor skills that were lost as dopamine neurons died.

A group of 20 young adult monkeys were first trained to pick fruit pieces out of small cups and timed on each effort. After learning the task all the monkeys received injections of MPTP, a drug that specifically kills dopamine neurons. MPTP destroys 90 percent of the dopamine neurons in the nigra-striatal system, says Kordower.

The 10 monkeys with the most severe Parkinson-like symptoms—the crooked arm posture and the dragging leg—were then chosen to receive the GDNF treatment. Half of these monkeys received lentivirus with the GDNF gene while the other half received a virus carrying a control gene.

After MPTP, the monkeys that received the control gene were often completely incapable of retrieving the fruit. Those that did attempt the task exceeded the allotted time of 30 seconds. In contrast, three of the four monkeys that were the recipients of GDNF performed the task in nearly the normal time. After assessing the improvement in arm movements, researchers studied the brain of each monkey to see if the improvement was mirrored by survival of dopamine neurons.

"Three animals out of four showed tremendous functional recovery and had outstanding protection of neurons in both the substantia nigra and the striatum," says Kodower. The monkey that did not recover on the fruit-picking task lacked protection in the striatum. Cell bodies of the dopamine neurons originate in the substantia nigra but they target and connect with other neurons in the striatum. "Special care will have to be taken to make sure this area is protected because it seems very important in controlling the extent of recovery. We really need to protect the target," says Kordower.

Kordower thinks that GDNF could be in clinical trials in 3 to 5 years, but believes that the gene needs to be under tight control. "We need to be able to control GDNF, to turn the gene on and off, so that dopamine can be controlled," says Kordower.

"You can't just put a potent factor like GDNF in a human brain at high levels without knowing what it can do. GDNF will act on other neurons and other dopamine neurons in other parts of the brain that play roles in cognition, depression and schizophrenia. So it is important to regulate where and how much GDNF is given to a patient," says Bohn.

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Kordower, J.H. et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 290, 767-773 (October 27, 2000).
Bohn, M.C. Parkinson's disease: A neurodegenerative disease particularly amenable to gene therapy. Mol Ther 1, 494-496 (June 2000).

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