Gene Therapy May Offer Hope in Parkinson's Treatment
Paul Recer,
AP Science Writer

5:18 PM EDT; October 26, 2000; Washington, D.C.(AP) -- A gene therapy experiment relieved severe symptoms of Parkinson's Disease in monkeys and experts say the technique offers promise for treating the 1.2 million Americans who suffer from the disease, experts say. A virus that had been joined with a gene that prompts production of dopamine, a chemical neurotransmitter, was injected into the brains of monkeys who had chemically induced Parkinson's Disease. Three monkeys that had severe symptoms of Parkinson's were restored to near normal by the gene therapy, said Jeffrey H. Kordower, first author of a study appearing tomorrow in the journal Science.

"We are able to stop the disease in its tracks and to keep it from progressing," said Kordower, the Director of the Research Center for Brain Repair at the Rush Presbyterian-St. Luke's Medical Center in Chicago. "The experiment showed dramatic protective effects," said Dr. Ted M. Dawson, head of the Parkinson's Disease Research Center at Johns Hopkins University Medical Center. "It is promising, but I would be only cautiously optimistic."

Parkinson's Disease, which affects about 1.2 million Americans, is a progressive disorder that affects brain cells that make dopamine. The loss of dopamine causes the classic Parkinson's symptoms: trembling, slow and stiff movement of limbs, a halting walk, speech difficulties and loss of balance. The etiology of the disease is unknown, and there is currently no cure. "Before the gene therapy could be tried in humans, questions about safety would have to be answered," Dawson said.

Dr. Mark H. Tuszynski, head of a brain disorder research center at the University of California, San Diego, said the experiment in monkeys was "fascinating" and offers the promise of "a very attractive therapy." He said, however, that "it is not known whether the brain cells affected by the chemically induced Parkinson's in monkeys are precisely the same as those affected by the actual disease in humans."

Kordower said a separate safety study is under way in monkeys, and when that is completed in about six months, an application for human clinical trials would be prepared for presentation to the Food and Drug Administration. "If all of the studies go smoothly," said Kordower, "the gene therapy could be ready for human testing in three to five years."

In the experiment, researchers Patrick Aebischer and Nicole Deglon at the Lausanne University Medical School in Switzerland altered a virus so it carried a human gene for a brain chemical called Glial-Derived Neurotrophic Factor (GDNF). This chemical prompts the production of dopamine. The virus also was modified, so it would not cause an infection. The altered virus was injected into the brains of aged monkeys. Autopsies later showed the gene caused brain cells to make dopamine and halted the normal degeneration of brain cells. In effect, said Kordower, the GDNF gene restored parts of the aged brains to a "youthful" condition, including an increase in the production of dopamine.

Kordower said the researchers then injected a group of Rhesus monkeys with a drug, MPTP, that artificially induces Parkinson's disease symptoms in both monkeys and humans. Ten of the monkeys developed slow movement and other symptoms of the disease. Five of the monkeys were then given GDNF gene therapy injections into the brain. Five others were given a placebo. One monkey in each group died, for unknown reasons, following the injections. Of the four remaining monkeys in the gene therapy group, three were totally relieved of the Parkinson's symptoms. The four control monkeys continued to show signs of the disease and became "severely impaired," said Kordower. He said the beneficial effect lasted for at least eight months.

The monkeys were then killed for a detailed histological analysis of their brains. In the treated monkeys, the analysis showed the brain's dopamine production cells were protected and there was an increase in levels of dopamine. "Brain cells in the control monkeys showed signs of degeneration," he said.

Among the Americans with Parkinson's, only about 15 percent of the patients are diagnosed before the age of 50. About one out of every 100 persons past the age of 60 has the disease, experts say.

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Abstract from Science

Jeffrey H. Kordower,1* Marina E. Emborg,1 Jocelyne Bloch,2 Shuang Y. Ma,1 Yaping Chu,1 Liza Leventhal,1 Jodi McBride,1 Er-Yun Chen,1 Stéphane Palfi,1 Ben Zion Roitberg,1 W. Douglas Brown,4 James E. Holden,34 Robert Pyzalski,4 Michael D. Taylor,3 Paul Carvey,5 ZaoDung Ling,5 Didier Trono,6 Philippe Hantraye,7 Nicole Déglon,2 and Patrick Aebischer28, "Neurodegeneration Prevented by Lentiviral Vector Delivery of GDNF in Primate Models of Parkinson's Disease," Science, Vol. 290, pp. 767-773 (October 27, 2000).

1. Department of Neurological Sciences and
5 Department of Pharmacology, Rush Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA.
2. Division of Surgical Research and Gene Therapy Center, Lausanne University Medical School, Lausanne, Switzerland.
3. Department of Medical Physics and
4 Department of Radiology, University of Wisconsin, Madison, WI 53706, USA.
6. Department of Genetics and Microbiology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
7. Commissariat a l'Energie Atomique (CEA), CNRS, Unite de Recherche Associe (URA), 2210 Service Hospitalier Frederic Joliot, CEA, Direction des Sciences du Vivant (DSV), Departement de Recherche Medicale (DRM), Orsay cedex, France.
8. Swiss Federal Institute of Technology, EPFL, Lausanne, Switzerland.
* To whom correspondence should be addressed. E-mail: .


Lentiviral delivery of glial cell line-derived neurotrophic factor (lenti-GDNF) was tested for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson's disease (PD). We injected lenti-GDNF into the striatum and substantia nigra of non-lesioned aged rhesus monkeys or young adult rhesus monkeys treated one week prior with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. These data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.