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MAJOR ADVANCES IN GENETICS, ENVIRONMENTAL RISK FACTORS FOR PARKINSON DISEASE

Eastman, Peggy

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WASHINGTON—New research on Parkinson disease (PD) could have major implications for its prevention, diagnosis, and treatment, leading PD investigators said at a briefing here sponsored by the NINDS in October.

“We have yet to cure any neurodegenerative disease, but I do believe Parkinson disease is at the forefront” in this effort, said NINDS Director Story C. Landis, PhD. She said that the scientific understanding of PD – even though the cause is unknown – has advanced to the point where halting and preventing it are “realistic goals.” Specifically, she cited new research on genetics, environmental factors, stem cells, and neuroprotective factors. (See “Genes, Proteins and Regions Implicated in Parkinson Disease”, page 40.)

“We had never thought of PD as a genetic disease,” said Dr. Landis, “but that is changing.” She cited the Parkinson's Disease Gene Therapy Study Group, a NINDS-supported consortium that is evaluating dopaminergic enzyme gene therapy and neurotrophic gene therapy in animal models of PD. At the forthcoming World Parkinson Congress in Washington, DC (February 24–26,2006), several papers will feature genes and PD, she noted.

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INTERPLAY OF GENETICS AND ENVIRONMENT

The gene story in PD is complex, and the disease does not run true in families through multiple generations except for rare cases, said J. Timothy Greenamyre, MD, PhD, Professor of Neurology; Director of the Pittsburgh Institute for Neurodegenerative Diseases; and Chair and Chief of Movement Disorders at the University of Pittsburgh Medical Center. Dr. Greenamyre noted that most cases of PD – like other neurodegenerative diseases – are likely to result from a combination of genetic susceptibility and the environment. “Genetics loads the gun, but the environment pulls the trigger,” he said.

He noted that farmers, who have higher exposures to pesticides, have a three- to seven-fold higher risk of developing PD than the general population. Dr. Greenamyre cited MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine), an environmental toxin that contaminated some street drugs of abuse and caused a Parkinson-like syndrome in drug users. MPTP is structurally similar to some pesticides, and an oxidized breakdown product of MPTP, MPP+, is toxic to the substantia nigra neurons affected by PD. Dr. Greenamyre also cited other neurotoxins such as the herbicide paraquat and the pesticide rotenone, which is commonly sold in garden supply stores. Rotenone is used to kill nuisance fish such as the snakehead, and causes neurodegenerative pathology in rats similar to that of PD, he said.

“The current thinking is that Parkinson disease is unlikely to be one disorder, and is likely to be heterogeneous,” said Robert L. Nussbaum, MD, Chief of the Genetic Disease Research Branch of the NIH National Human Genome Research Institute.

Dr. Nussbaum said that by studying the rare families in which PD follows Mendelian inheritance patterns, much can be learned about PD in general. “They give clues,” he said of the inheritance patterns. Further, said Dr. Nussbaum, the gene discoveries in PD could be drug targets. The gene story in PD is an unfinished one. “There could be other genes that we don't know about yet,” he said.

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NEW TARGETS FOR INTERVENTION

“I'm optimistic that many pathways will be discovered,” said Peter T. Lansbury, Jr., PhD, Professor of Neurology at Harvard Medical School and Director of the Morris K. Udall Parkinson's Disease Research Center of Excellence at Brigham and Women's Hospital in Boston. These pathways will offer targets for intervention. But, he said, there needs to be a continuing emphasis on translating new discoveries into practice. He noted that PD does not produce symptoms until an estimated 70 percent of the dopaminergic neurons have been lost. What is needed, he said, is a disease-modifying drug that could reduce the prevalence of debilitating PD before symptoms are clinically apparent.

A better test for earlier diagnosis of PD would help move the field along, speakers agreed. Although brain imaging is available (PET showing glucose uptake, for example), “We'd like a rapid test to screen and treat patients for PD before it is symptomatic,” said Dr. Lansbury. He said such a test could be cost-effective, because it could reduce the $5 billion or more spent in the US on PD every year. Today, “there are no approved drugs that modify the progression of PD,” said Dr. Lansbury. Levodopa and other available drugs can provide initial symptomatic relief, but do not stop the loss of neurons in PD.

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MARKET INCENTIVES FOR DEVELOPMENT

“It's a huge market,” Dr. Lansbury said of a new disease-modifying drug for PD, but he noted that specific incentives are needed to induce pharmaceutical companies to take the risk to research and develop such a drug in the post-rofecoxib (Vioxx) era of intensified scrutiny of drug safety and efficacy.

“The slow progression of PD means that clinical trials will take a long time and will be expensive,” he said. “We cannot change the market incentives, but we can change the rules,” said Dr. Lansbury. He added that the laws that regulate drug development and marketing are outmoded and must be revised to reaffirm their original intent

Figure. Dr. Story C....
Figure. Dr. Story C....
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Asked by Neurology Today for specific suggestions, Dr. Lansbury suggested a broadening of the 1983 Orphan Drug Act to make it more flexible and to encompass more diseases than those that affect 200,000 people or less, which is now the guideline. He called the number 200,000 “arbitrary.” The act could be modified to give a pharmaceutical company tax breaks to develop a drug for an illness if it is first in that arena, he added. “There have to be incentives for a trailblazer,” he said. “If you're second in, no.” Dr. Lansbury said new policies and regulations to stimulate drug development should be introduced “on a case-by-case basis.”

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NEURON REPLACEMENT

Neuron replacement and neurotrophins have created a burgeoning field of PD research, said Clive Svendsen, PhD, Professor of Neurology and Anatomy at the University of Wisconsin-Madison; Director of the NIH-funded Stem Cell Training Program; and Co-director of the Wisconsin Regenerative Medicine Program. While dopamine neural transplantation is especially promising for PD, said Dr. Svendsen, it is ethically difficult because the replacement neurons come from human fetuses.

“We need another source of dopamine neurons before we can move forward,” he said. “While a researcher can grow embryonic dopamine cells almost indefinitely, a laboratory technique with ‘great potential’ to replace fetal tissue, it is hard to get these cells to survive in transplantation, and they can form teratomas. It is difficult to restore full circuits in PD.” Disappointingly, he said, the first fetal brain transplant patients developed dyskinesias.

Dr. Svendsen, who was involved in the world's first clinical trial to infuse the growth factor glial cell line-derived neurotrophic factor (GDNF) directly into the brain tissue of PD patients, said that this technique also holds promise for PD. Because of the blood-brain barrier, an oral form of GDNF will not work, Dr. Svendsen noted, so his team has injected GDNF directly into the brain, where it has a “fertilizer effect” on the growth of dopamine neurons. He said that GDNF can also be inserted into the brain via gene therapy, using a genetically engineered virus that programs the cells to make GDNF. This technique is being studied in animals. But the problem with using a viral vector, said Dr. Svendsen, is that “you can't switch it off once you put it in, so it has to be safe.” Also under study, he said, is a small GDNF pump inserted under the skin and a plastic capsule filled with GDNF and inserted into the brain. “A nice advantage is that you can take the capsule out,” he said.

GDNF, which is made by human stem cells, is not attractive to pharmaceutical companies, said Dr. Svendsen, pointing out that Amgen, Inc. – which was supporting research on GDNF – has stopped GDNF clinical trials around the world. “I think this is typical,” said Dr. Svendsen, noting that it is difficult to see how a company can make money from stem cells that produce GDNF.

Figure. Dr. J. Timot...
Figure. Dr. J. Timot...
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A more comprehensive overview of research advances will be reported at the upcoming World Parkinson Congress. For more information, visit www.worldpdcongress.org.

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GENES, PROTEINS, AND REGIONS IMPLICATED IN PARKINSON DISEASE

Following are some (but not all) of the genes, proteins, and regions associated with Parkinson disease:

* Alpha-synuclein, the first PD-related gene to be identified

* Parkin, a gene discovered through studies on a rare, juvenile-onset form of PD

* DJ-1 (PARK7), a gene linked to another early-onset form of PD

* PINK1 (PARK6), a gene found in several families with PD

* DRDN, a gene implicated in a late-onset form of PD

* UCH-L1 (PARK5), a gene that is a member of the ubiquitin-proteasome system that helps identify misfolded proteins for breakdown

* Synphilin-1, a protein that interacts with alpha-synuclein and promotes the formation of cellular inclusions similar to Lewy bodies

* Tau, a protein constituent of microtubules whose aberrations may contribute to sporadic PD

* PACRG, a gene which interacts with parkin, seems to be part of the protein degradation system, and appears to be a component of Lewy bodies

* PARK3, PARK9, PARK10 and PARK11, chromosomal regions which have been implicated in PD, but the regions have not been narrowed down to specific genes

* GSTO-1 and GSTO-2, genes that appear to play a role in the brain inflammation found in patients with PD

* Fibroblast growth factor 2 (FGF2), a gene that helps to maintain neurons which, when mutated, may be a risk factor for PD

* Apolipoprotein E, whose genetic variations appear to influence the age of onset for PD as they do for Alzheimer's disease

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ARTICLE IN BRIEF

✓In a prelude to the World Parkinson Congress in February, the NINDS convened leading experts in Parkinson disease to highlight research advances that have implications for diagnosis, prevention, and treatment.

©2005 American Academy of Neurology

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