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Halted Alzheimer's Vaccine Was on Right Track

Trial of shots stopped over concerns of brain inflammation

MONDAY, Oct. 14, 2002 (HealthDayNews) -- A little fine-tuning may salvage an Alzheimer's vaccine that was being tested in patients until many developed severe brain inflammation earlier this year.

That's the conclusion of two new studies, one in mice and one in people, which suggest the stalled inoculation not only appears to work but can be made transparent to reactionary immune cells.

The troubled vaccine, called AN-1792, was designed to provoke an immune reaction against amyloid-beta plaques, the hard protein clusters whose buildup in the brain is believed to cause Alzheimer's. It did so by priming the body's defenses with amyloid-beta protein, teaching them to seek out and destroy the substance.

Tests on mice reportedly had suggested the vaccine could slow or even prevent development of the dementia disease.

But AN-1792's maker, Elan Corp., of Dublin, abandoned clinical trials with the injection earlier this year after 17 people receiving the shot developed meningoencephalitis. Elan and its partner, Wyeth-Ayerst Laboratories, a division of American Home Products Corp., say roughly 300 people with Alzheimer's in Europe and the United States received the vaccine before the studies were halted.

Yet the latest work, appearing yesterday on the Nature Medicine Web site, indicates that AN-1792 still has potential -- at least in some form.

In one study, researchers in Canada and Germany tried to make an end-run around the chief problem with AN-1792 -- the fact that it can provoke such a hostile reaction from the immune system's T-cells. That information was available to Elan researchers when the drug was being developed, in the form of an Internet library of proteins known to aggravate those two cell types.

However, one end of the protein from which the vaccine was derived turns out not to have any offenders on that list. So a team led by JoAnne McLaurin, an Alzheimer's expert at the University of Toronto, tested that short segment of the molecule in mice with a form of the degenerative brain disease.

Not only did the modified vaccine prevent the buildup of plaques, but it cleared some of those fibers already present in the animals. It also improved some of the spatial problems the rodents had developed as a result of their condition.

McLaurin belongs to the camp of brain researchers who believe Alzheimer's results not from plaque buildup itself but from the short-lived toxic middle molecules that make up the strands, which are precisely what the vaccine targets. So in theory, breaking plaques into their constituents might cause more harm than good -- but it didn't. "The animals didn't have a decrease in functioning. That would suggest that we aren't creating something toxic," she says.

McLaurin says the experiment supports pursuing an Alzheimer's vaccine such as AN-1792, but it may also lead to highly specific, small-molecule drugs to treat the condition.

The second study, by researchers in Switzerland, looked at whether the Elan vaccine had taken in two dozen Alzheimer's patients. Each of the men and women was given an initial injection and a booster shot four weeks later, while six others received dummy inoculations.

Roughly two months later, most of the vaccinated patients had developed high levels of blood proteins, or antibodies, against brain plaques, suggesting the shots were doing their job. The antibodies were specific to the amyloid-beta proteins in the plaques of dementia patients, as well as to those in their more diffuse deposits and blood vessels. But they did not seem to have an affinity for amyloid-beta in the neurons of healthy people.

One of the patients developed brain inflammation after getting immunized, but recovered.

Dr. Ivan Lieberburg, Elan's chief science officer, says the two studies were "very supportive" of the company's approach. And the Swiss paper shows that simply stimulating the body to make antibodies against amyloid-beta, even loads of them, isn't what triggered the brain inflammation, he adds.

While AN-1792 will most likely become a medical museum piece, Elan and Wyeth have been working on "four or five" related vaccines and antibody drugs. Among them is one like that McLaurin's group tested, he says.

Researchers continue to follow the patients in the original trial and will complete their one-year assessment of the vaccine in a few months, Lieberburg said. In the meantime, it's too soon to say how effective the shots have been. But since the full schedule of inoculations was as many as eight during the yearlong trial, and no one received more than three, "the probability is reduced that we will see anything dramatic," he adds.

Alzheimer's disease affects an estimated 4 million Americans, a number projected to hit 15 million by the middle of this century, according to the Alzheimer's Association. Drugs can help slow the progression of dementia by a few months, but doctors have yet to find a cure for the degenerative illness.

In unrelated work being reported today at a meeting of the American Neurological Association, researchers said the Alzheimer's drug galantamine can improve mental function in patients with dementia caused by vessel damage in the brain. Galantamine blocks the action of an enzyme called cholinesterase, which breaks down an important brain messenger molecule involved in cognition and memory.

What To Do

For more on Alzheimer's disease, try the Alzheimer's Association or the National Institutes of Health.

SOURCES: JoAnne McLaurin, Ph.D., assistant professor, Center for Research in Neurodegenerative Diseases, University of Toronto; Ivan Lieberburg, M.D., Ph.D., chief scientific and medical officer, Elan Corp., San Francisco; November 2002 Nature Medicine
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