Scientists Piecing Alzheimer's Puzzle
By: Source: AARP Bulletin Today Date Posted: 2003-09-02 15:40:00-04:00
After years of frustrating research, scientists are buoyed by a new optimism about finding a cure for Alzheimer's disease.
Research has moved to a critical new stage: This brain-wasting disease is finally beginning to yield its intimate secrets to laboratory science. Unlocking these secrets could lead to effective new drugs and even a vaccine to prevent the relentless destruction of brain cells that causes the memory loss and confusion of Alzheimer's.
In a major development, later this year some experimental therapies previously tested only on laboratory animals will at last be tested on humans. Even so, drugs and vaccines will not be available to the public soon; indeed, the testing process may take four to eight years.
| The testing process for experimental therapies may take four to eight years. |
Nevertheless, this new phase in testing is a milestone, scientists say. "There's some real excitement, because for the first time we can think of prevention and cure; the message is an upbeat one," says Dennis J. Selkoe, M.D., professor of neurology and neuroscience at Harvard Medical School.
Selkoe calls the year 2000, this first year of the new millennium, "the beginning of the era of Alzheimer's therapeutics." He adds, "All that research is beginning to pay off. We're not quite there yet, but we're going to get there very soon."
Resulting from the loss of nerve cells in the brain, Alzheimer's right now is an incurable disease that impairs a person's ability to reason, remember or control behavior. It afflicts about 4 million Americans, some 3 million of whom live at home and are cared for by family.
Some researchers now believe they are getting closer to a way to prevent, and possibly even cure, Alzheimer's. Fueling this optimism, they say, are these developments: new ideas on how to combat key enzymes that contribute to the disease and on how to immunize people against a protein that becomes abnormal.
Another major development is the emergence of human gene therapy to revitalize damaged brain cells.
Two of these new developments—enzyme-blocking therapy and gene therapy—will be tested in human studies this year. Scientists are particularly excited by new enzyme research that they say could speed the development of drugs to block or even reverse brain cell degeneration.
After years of research, scientists at Amgen Inc., a biotechnology company based in Thousand Oaks, Calif., announced recently that they had identified the enzyme beta-secretase, which plays a key role in the buildup of abnormal plaques in the brain. These plaques, from a protein called beta amyloid, destroy brain cells.
Amgen is searching for agents that can block beta-secretase, and this year will test these compounds in laboratory animals. If all goes well, the tests could be a prelude to tests on humans in several years.
But some tests are already being done on human subjects. Last year scientists at several research centers published studies on gamma-secretase, which is also thought to play a key role in the abnormal buildup of the protein beta amyloid.
Bristol-Myers Squibb Co., for example, will soon begin human testing of a gamma-secretase blocker to prevent beta amyloid plaques. "The trials will be done in small groups of patients," a company representative said. "Larger-scale clinical trials will follow after those studies."
Noted Belgian and German scientists writing recently in the journal Nature called the new work on enzymes "a firm base for drug development."
Some scientists remain cautious. They warn that the beta amyloid buildup hasn't been proven to be the cause of Alzheimer's disease, although they see it as a strong suspect.
Even optimists agree that blocking beta- or gamma-secretase may not be the complete answer in Alzheimer's; scientists won't know until they get the results of testing these inhibitors in human volunteers.
For that matter, scientists don't yet know if blocking these enzymes—which also have normal functions—could do harm. In the case of gamma-secretase, there is some evidence that blocking this enzyme could lead to reduced immunity against disease and anemia (a red blood cell disorder that can cause dizziness and heart problems).
"We don't know much about what gamma-secretase does in its real life," says Bill Thies, vice president of medical and scientific affairs for the Alzheimer's Association, a nonprofit group based in Chicago. For that reason, he notes, the monitoring of people taking the first gamma-secretase inhibitors will be intense.
"The beta amyloid protein is there for a reason," notes Stanley J. Birge, M.D., associate professor of medicine in the division of geriatrics and gerontology at Washington University School of Medicine in St. Louis. So scientists must do their work very carefully, he cautions.
But if an abnormality leading to beta amyloid plaques is the key to Alzheimer's, he says, enzyme blockers are "certainly a doable way of preventing the buildup of that protein."
Scientists also are working toward immunizing people against Alzheimer's. Researchers at the Elan Corp., based in Ireland, are relying on the basic principle of a vaccine: giving a disease-causing substance to animals to stimulate the immune system to mount a defense against it.
Working with "transgenic" mice that had been altered in the laboratory to develop a form of Alzheimer's (mice don't naturally get it), the researchers gave one group a vaccine made from beta amyloid called AN-1792; other groups received no vaccine.
The immunized mice developed no detectable beta amyloid plaques in their brains at all, while the untreated mice had a steady buildup of beta amyloid plaques.
Even more promising, says Birge, is that when mice that already had beta amyloid plaques were treated with AN-1792 for seven months, their abnormal plaques receded. "This is not pie in the sky," adds Birge. If it works in humans, such a vaccine might both prevent Alzheimer's and treat it in its early stages. Asked when the vaccine might be ready for human testing, an Elan spokesperson said it would be "premature" to give such a timeline.
Another promising line of research is gene therapy to repair damaged brain cells. Working with monkeys, Mark H. Tuszynski, M.D., associate professor of neurosciences at the University of California at San Diego, has shown he can reverse brain cell degeneration with a new kind of human gene therapy.
"These findings give us a new avenue to pursue" in trying to improve the "attention, the ability to focus on multiple tasks at once and the overall efficiency of thought processes" in both the normal and the Alzheimer's-diseased brain, he says.
Tuszynski has received approval from the U.S. Food and Drug Administration to test his form of gene therapy in humans with Alzheimer's.
One hopeful subject is retired schoolteacher Bud Schenker, 73, who has the forgetfulness of early Alzheimer's. He appeared on a national television newscast recently to explain why he volunteered for an upcoming gene therapy study in San Diego.
"I'm looking forward to it," he said. "It would be a godsend, because I want to get back to, as close to, normalcy as I can."
Tuszynski is now awaiting the approval he wants from the Recombinant DNA Advisory Committee of the National Institutes of Health and expects to begin his human studies in about eight people with early stages of Alzheimer's this spring.
What Tuszynski did—in collaboration with the Salk Institute for Biological Studies, La Jolla, Calif.—was to implant genetically modified cells that deliver human nerve growth factor (NGF) into the brains of monkeys that showed age-related declines due to atrophied brain cells.
NGF is a substance that nourishes brain cells. In the tests, NGF revived degenerated brain cells linked to memory, selective attention and other key factors in thinking.
In his experimental human studies, Tuszynski will inject genetically modified cells that produce NGF through a needle into the brains of human volunteers. The first studies will be done to determine the safety of this procedure.
"This is a technical tour de force," says Thies of the Alzheimer's Association. "It's a very high-tech sort of answer." Whether this provocative form of brain gene therapy proves safe, effective and practical for larger numbers of Alzheimer's patients remains to be studied.
In addition to plaques, the brains of some people with Alzheimer's may have another feature: tangles. These tangles are made of abnormal, twisted strands of yet another protein, called tau. Some researchers are concentrating their efforts on trying to find a way to block tau.
Scientists funded by the National Institute on Aging at the University of Pennsylvania's Center for Neurodegenerative Disease Research in Philadelphia recently took a leap forward when they produced genetically engineered mice that make a form of tau. These mice develop abnormal tau deposits in their brains; by studying what happens to them, scientists may discover new anti-tangle treatments for human Alzheimer's.
Taken together, the new research on Alzheimer's disease represents a positive step forward, says the Alzheimer's Association's Thies. "The amount of basic information that we've seen about Alzheimer's disease in the last few years has just exploded."
This article previously appeared in the AARP Bulletin. Since its original publication, there may have been some medical developments in this area. Therefore, consult your physician for the latest information and advice on treating this particular condition. The information in this article is intended only to describe this medical issue in general terms. This information should not be used as advice regarding your particular condition. Only your physician can give you proper medical advice.
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