(Embryonic stem cell transplants reverse symptoms in mice.)- San Francisco, Feb. 16th, 2001, Associated Press


Scientists may be on the brink of curing Parkinson's disease using transplanted embryonic stemcells, but where and when that new treatment is tested in humans depends on unresolved political decisions, researchers suggested Friday.

Dr. Ole Isacson of Harvard Medical School and Dr. Ronald McKay of the National Institutes of Health said Friday they have both 'cured' Parkinson's in mice and rats, using stem cells removed from embryos of laboratory animals. In a report at the national meeting of the American Association for the Advancement of Science, Isacson said mouse and rat embryonic cells, after careful processing, can be grafted into the animal brains where they transform into replacements for cells killed by Parkinson's. "In mouse models (laboratory tests) these cells have restored function," said Isacson.
Using a slightly different technique, McKay said his NIH lab has also prompted mouse embryonic stem cells that are lacking in Parkinson's. McKay and Isacson said researchers are almost ready to test the technique in humans, but social and political issues must be resolved in the U.S. before that step can be taken in the country. At the same time, McKay said it may happen soon in Britain, France or the Netherlands, as those countries are adopting policies to advance embryonic stem cell research.

"It's going to happen, but just where may depend on social and political issues," McKay said. "There is a great sense of optimism shared by many people in the field right now."

In the U.S. some groups, including some members of Congress, oppose the use of embryonic stem cells in research because gathering the cells requires the death of a human embryo.


"Facts About Parkinsons' Disease"

New NIH guidelines permit federal funding of such stem cell research, but only if the cells are extracted from embryos in labs not recieving federal funding. Tommy Thompson, the new secretary of Health and Human Services that oversees NIH, said he is reviewing the policy on embryonic stem cells research. "Some researchers have sought NIH funds to conduct embryonic stem cell studies, but no grants have been issued," said Mckay.

What are stem cells?
Stem cells are master cells that have the ability to differentiate into other cell types, including those in the brain, heart, bones, muscles and skin.

Sources: Reuters, University Of Wisconsin, Madison.


More than one million Americans have been diagnosed with Parkinson's, a disease caused by the death of brain cells that produce dopamine, a key nerve chemical. When patients lose about 80% of these cells, they develop, the classic Parkinson's symptoms: tremors and rigidity.

Parkinson's can be treated with L-dopa, a drug that makes dopamine in the brain. But L-dopa is effective for only a short time and after that the disease progresses.

"Limited experiments using brain cells from aborted fetuses have stabilized patients for up to 12 years," Isacson said. The transplanted cells convert to dopamine-producing cells, replacing those lacking in patients with Parkinson's.
But using tissue from aborted fetuses in research also is opposed by many groups. And because of limited availability and for technical reasons, fetal tissue is not considered ideal for treating Parkinson's.
The best hope, said the researchers, are the embryonic stem cells. These are master cells that can be coaxed to transform into virtually any type of tissue in the body.

"Embryonic stem cells can be grown in great numbers, making them readily available for treating thousands of patients," the researchers said.

"You can generate embryonic stem cells with huge efficiencies," said McKay.

McKay said his lab has found ways to cause mouse embryonic stem cells to change into the dopamine-producing cells lacking in Parkinson's.

"We can take the embryonic stem cells through a series of transitions until they become the dopamine cells," said McKay.

Isacson said his lab injects into the brain specific cells extracted from the embryo and that a natural process in the brain then transforms them into dopamine producers.

"The cells organize themselves to become very fundamental," he said. "We see the cells bahving in a way to reverse the symptoms (of Parkinson's) in the mouse and rat."

"Solving The Parkinson's Puzzle"
'Scientists report promising results in research to help cure disease'


Experimental brain-cell transplants for Parkinson's disease are starting to show some encouraging results after more than a decade of fustration.

Brain experts have just reported the first, long-term follow-up studies of early transplant cases. At the same time, laboratory researchers are gaining ground on some important practical issues standing in the way of success.

All agree that better treatments are sorely needed. Parkinson's and similar movement disorders afflict some 1.5 million people in the United States.

Although the disease typically strikes people in their 50s and 60s, Parkinson's can show up in younger people, too. No one knows exactly what triggers the disease, marked by a progressive die-off of nerve cells that produce the neurotransmitter dopamine.

For most patients, the only current options are dopamine-replacing drugs, deep-brain electrical stimulators or pallidotomy, a surgical procedure, all of which can help ease symptoms, at least for awhile, but don't stop the underlying disease process.

"Something has to happen," said Philip Wong, a state government aditor in Fresno forced to seek an early retirement after he was diagnosed with Parkinson's three years ago.
"This disease is very difficult to accept."

He said he can already sense less reliable results from his current drug regimen. As for novel approaches such as brain-cell transplants, "I'm open-minded," he said. "You always want the research to go faster."

BRAIN CIRCUIT IMBALANCE

The neurons whose death leads to the symptoms are located deep in the brain stem in a region called the substantia nigra, from which they send out long branches to other parts of the midbrain. As the dopamine-producing cells diminish, the connections wither.

Soon, a chronic shortage of dopamine results in anb imbalance in the complicated brain circuits that guide the motor system. That gives rise to the classic symptoms of Parkinson's, including worsening tremor, slow movement and difficulty walking.

Fresh, dopamine-producing cells can be taken from aborted fetal tissue and placed directly into the midbrain. The idea is to give patients their own dopamine factories right where the neurotransmitter is needed.

Very few patients have tried the transplant approach, considered a highly experimental option available only as part of limited research efforts. Still, the latest evidence raises the prospect of a new era of surgical treatment for Parkinson's, as well as for other previously incurable neurological disorders.

"Parkinson's will be the first," said William J. Marks, a neurologist at the University of California at San Francisco.
Marks also heads a Parkinson's center at the San Francisco VA hospital.

Experts say someday it may be possible to repair virtually any damaged part of the nervous system, dropping in new components to replace worn-out parts, using a sophisticated array of microbiological tricks to make sure things wire up properly.

"It sounds like science fiction, but we're moving very rapidly in that direction," said Ben Barres, professor of neurobiology at Stanford University.

Reporting in last month's issue of Nature Neuroscience, doctors in Europe reported that transplanted cells in the brain of one Parkinson's patient were still functioning 10 years after the operation was performed. That strongly suggested that whatever was causing the patient's own cells to die off did not seem to affect the transplanted cells.

"Scientifically, that's a very important result," said William Langston, a doctor who founded and is director of the Parkinson's Institute, a research and treatment center in Sunnyvale. "It tells us for the first time that whatever is killing the cells in parkinson's disease is not lurking about in the brain."

The next step is to dtermine just how much a patient's symptoms improve from undergoing a transplant procedure. Results have been mixed, but substantial gains have been noted in some transplant cases, including a less pronounced tremor, improved gait and less need for drugs.

Benefits are less clear in older patients, however. Researchers are expecting more definitive results soon from a major clinical study in the United States.

Meanwhile, scientists are searching for other sources of transplant material, including snimal cells or bio-engineered stem cells--a special, all-purpose kind of cell that can be tweaked into developing into a dopamine-producing neuron.

One other novel possibility is to use specialized cells found in the neck, which are equipped to check oxygen content in the blood going to the brain. As it happens, these cells appear to have near-magical dopamine-pumping abilities. If early results in animal experiments experiments bear out in people, it might be possible for patients to provide their own graft material.

The fetal cells now used must be harvested at a certain point in the development process when the neurons are poised to grow vigorous connections. It generally requires four or five aborted fetuses to provide enough cells for a single Parkinson's transplant.

NEED FOR CELL SOURCES

Even without opposition on ethical grounds, everyone recognizes that transplants will never become widely available if aborted fetuses are the only source of fresh neurons.

"The big issue now is finding alternative cell sources," Langston said. "There's tremendous interest in the possibilities of stem cells, but we're very early in the process."

Another new study has shown that it may be possible to dramatically increase the survival of transplanted cells, the vast majority which, through current methods, immediately die off. Even a modest improvement in cell-transplant survival could make all the difference for some patients.

Parkinson's may be a special case, Barres noted, but the fundamental questions may have wide implications.

"You've got to get the new neurons in there, in the right place, and then you have to get them to grow new connections that are fucntional," he said.
"That's not science fiction at all," he added. "It's very feasible. We're juts trying now to work out the mechanisms."

In a commentary published last week in the journal Nature, Barres and Stanford post-doctoral candidate Jeffrey Goldberg noted the significance of a new gene study identifying how the insulating myelin sheaths surrounding large bundles of nerve fibers produce a protein that inhibits nerve-cell regeneration.

This inhibitory protein, a product of a gene dubbed "Nogo", is thought to play a useful role in adults by preventing willy-nilly brain-cell branching, thus stabilizing the circuitry that underlies mental function. But the same protein can cause probklems when doctors are trying to coax a nerve cell to make the necessary connections.

Discovery of the Nogo protein is a landmark step on a long road toward new treatments for patients suffering from many neurological conditions, including spinal-cord injury and stroke," Barres and Goldberg concluded.

OVERCOMING PARKINSON'S DISEASE
Parkinson's disease afflicts an estimated 1.5 million people in the United States. Symptoms are caused by the death of nerve cells that produce the neurotransmitter dopamine. There is no cure, but results with experimental brain-cell transplants are generating some optimism.

HOW NEURAL TRANSPLANTS WORK:
Fresh dopamine-producing nerve cells are obtained from aborted fetuses. In hopes of avoiding the ethical controversies and limited availability of fetal tissue, scientists are experimenting with bioengineered stem cells that turn into nerve cells.

About 60 000 cells are implanted in the putmen, the part of the brain to which cells in the substantia nigra project.

Latest studies shwo that transplanted cells can function normally for as long as 10 years, although transplants often fail in older patients. A clear benefit in terms of motor function has yet to be proven.

PARKINSON'S FACTS:
Total cases in U.S. : 1.5 million
New diagnoses: 60 000 per year, rising as population ages
Symptoms: Worsening tremor and loss of control over movement.
Current treatments: Drugs can be used to replenish the brain's supply of dopamine and improve it's uptake, but the benefits tend to wear off with long-term use.

Source: Parkinson's Institute, National Institutes of Health. Wiliams and Wilkins; Neuroscience: Exploring the Brain by Mark Bear and Chronicle research

'NIH RESEARCHERS FIND FIRST PARKINSON'S DISEASE GENE'

Betheseda,MD- Scientists at the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH) have for the first time precisely identified a gene abnormality that causes some cases of Parkinson's disease. The gene spells out instructions for a protein called alpha synuclein. In the abnormal version of the gene, the researchers found a mutation in a single base pair-one incorrect letter in the string of more than 400 that compose the instructions for making the protein. Because the normal gene plays a role in the function of nerve cells, the finding gives researchers a powerful new tool for understanding cellular abnormalities in Parkinson's disease and demonstrates a connection between Parkinson's disease research and research into other neurological disorders, such as Alzheimer's disease.

According to NHGRI's Dr. Mihael Polymeropoulos, the paper's lead author, "the finding opens completely new horizons in understanding the disease and interpreting the biology of the illness. Moreover, the finding will have an application in the not too distant future as a clinical research tool within families especially prone to Parkinson's disease and may permit us to design clinical studies for investigating drugs or other ways of postponing or offering protection from the illness."

The paper confirms last fall's report co-authored by the same NHGRI team that a predisposition to at least one form of Parkinson's disease is inherited and that the gene responsible was situated somewhere in a large region on the long arm of chromosome 4. Until that report, most experts believed that Parkinson's disease was probably due to unknown factors present in the environment.

"This finding could prove to be the most siginificant advance in our understanding of Parkinson's disease since the dopamine hypothesis was put in our minds in the mid 1960s. It is a good example of how we make progress towards the conquest of particular diseases by supporting a diversity of fundamental and clinical research. This discovery about Parkinson's disease also deepens our study of Alzheimer's disease, basic neuroscience, cell biology and genome research and gene mapping." says NIH director, Dr. Harold Varmus.

To find the gene, the scientists first studied members of a large family that came originally from Italy. Some had emigrated to the U.S. early in this century, and more than 60 family members on both sides of the Atlantic have been diagnosed with Parkinson's disease. Efforts to locate the gene intensified after a workshop on Parkinson's disease sponsered by the National Institute of Neurological Disroders and Strokes(NINDS).
At that meeting, which identified genetic research as an important area of opportunity, scientists from NIH met researchers at the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School in Piscataway, New Jersey, who had been investigating Parkinson's prone families for some time. Soon after, the NIH scientists, led by Dr. Polymeropoulos, began to carry out a genetic analysis of Parkinson's disease using DNA from patients identified and followed by an international team of researchers, including the Robert Wood Johnson team and Physicians at the University of Naples, Italy. With the help of collaborators at the University of Patras Medical School in Greece, the NHGRI researchers also studied 5 additional unrelated families of Greek origin with a hereditary form of the disease.

Using information provided by the Human Genome Project, NHGRI researchers rapidly located the mutation to a region of the genome containing approximately 100 genes. One of the genes already placed in this interval was alpha synuclein. The alpha synuclein gene was an excellent candidate for being a Parkinson's disease gene because previous research had already shown that the amyloid plaques of Alzheimer's disease patients contained fragments of the alpha synuclein protein. Considering its potential role in neurodegenerative disease, the researchers began looking at the precise sequence of alpha synuclein in normal and affected individuals. In the Italian family and three of the Greek families, the Parkinson's patients were found to possess an identical mutation in a single base pair of the alpha synuclein gene.

Parkinson's disease is characterized by deposits in the brain called Lewey bodies. The researchers hypothesize the mutation in the synuclein protein causes it to aggregate, thus attracting other proteins to form a deposit that damages the cell. A similar mechanism has been proposed for the production of amyloid plaques in Alzheimer's disease. The finding that Alzheimer's disease plaques contain a fragment of alpha synuclein further strengthens the idea that a common mechanism may be operating in both of these neurodegenerative diseases.

The NHGRI researchers suspect that the abnormal gene is responsible for a significant portion of familial Parkinson's disease with onset generally before the age of 60. It is not known how frequent alterations in this gene will be in later onset cases with less striking family history, though the same pathway has been identified to be involved in these four families may turn out to be abnormal in other patients as well. Alpha synuclein is actually a member of a group of similar synuclein genes in the human genome. The NHGRI scientists are now actively searching among patients with familial Parkinson's disease who do not possess this alpha synuclein gene, and other similar genes known to exist in the human genome, are expected to help scientists decipher additional causes of Parkinson's and perhaps shed light on other devastating and common brain disorders.
"For people with Parkinson's disease, this is a small but important step in a very long journey-hopefully leading to an understanding of the basic underlying defect in Parkinson's disease which causes the death or loss of function of the cells in the brain. If it results in a deeper understanding of how Parkinson's disease comes about, it may make us smarter in developing therapies. But it is important to stress that at this point there is no direct therapeutic result from this finding," says the paper's senior author, NHGRI's Dr. Robert Nussbaum.

Although the researchers caution that a test will provide limited information for most people, one near-term application for such a test in high-risk families will be in research aimed at developing ways of slowing or stabilizing the illness. Investigators are hoping that such preventive measures will eventually be useful in treating Parkinson's disease.

The discovery of the mutant alpha synuclein gene raises issues of genetic testing that have become increasingly familiar as the list of gene discoveries lengthens. The issues are especially similar to those that have arisen in connection with genetic testing for predisposition to other diseases that appear late in life, notably Alzheimer's disease and Huntington's disease.

"Discoveries like this reflect how rapid disease gene identification can be as the Human Genome Project has continued to mine the genome for its treasures," says NHGRI director Dr. Francis Collins. "As more gene sites are identified, it will become almost routine for disease gene hunters to find an already characterized gene waiting for them when they arrive at the neighbourhood they know is involved in a disease. But this discovery, which raises the possibility of identifying healthy individuals at future risk for illness, also underlines again how crucial it is they provide legislative protections against misuse of the information, especially in health insurance and employment."

"The results announced today highlight the importance-and-benefit-of bringing new ideas in to the field of Parkinson's disease research," says Dr. Zach W. Hal, Director of the NINDS. "The identity of this gene suggests an important new link between Parkinson's and Alzheimer's diseases, and may ultimately help us prevent or delay the cell death that is responsible for degenerative brain disease."

NHGRI oversees the NIH's role in the Human Genome Project, an international research effort to develop tools for gene discovery.