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Gene-Based Vaccines May Fight Alzheimer's

They slowed brain plaque build-up in mice, but success in humans will be real test, experts say

MONDAY, June 12, 2006 (HealthDay News) -- In what might prove a breakthrough against Alzheimer's disease, Japanese researchers have created a new gene-based vaccine that effectively treated mice with an animal form of the brain-robbing illness.

The new vaccine may be an important advance because it doesn't cause the side effects seen in other vaccines, according to Dr. Yoh Matsumoto, whose team developed and tested the vaccine at the Tokyo Metropolitan Institute for Neuroscience.

Matsumoto said his team is now testing the DNA vaccine on aged monkeys. "If we obtain satisfactory results, then we are ready for clinical trials," he said.

The findings appear in this week's issue of the Proceedings of the National Academy of Sciences.

The new vaccine targets genes responsible for the overproduction of amyloid-beta peptides, small proteins that form plaques in the brain. Many researchers believe the accumulation of these plaques is the root cause of Alzheimer's disease, although this theory is not universally accepted.

So-called anti-amyloid vaccines deliver amyloid peptide to the body to provoke an anti-amyloid immune response, priming the immune system to recognize and destroy the plaques later on.

"DNA vaccines are given by intramuscular injection, which stimulates the production of anti-amyloid-beta antibodies," Matsumoto said.

In the study, Matsumoto and his colleagues describe how they used two types of regimens -- preventive and therapeutic -- to test the vaccine's effectiveness in mice. During the preventive regimen, the mice started receiving injections at 3 to 4 months of age, before any plaques had developed. During the therapeutic regimen, the mice received injections starting at 12 months of age, six months after plaques started forming.

In the preventive part of the study, the researchers found that the vaccinated mice had 15.5 percent less plaque accumulation at seven months of age, and 38.5 percent less accumulation at 18 months of age than unvaccinated mice. In the therapeutic part of the study, they found that the vaccinated mice had 40 percent to 50 percent less plaque accumulation at 18 months of age than the unvaccinated mice.

Not all Alzheimer's vaccine research has worked well in humans, however. Another anti-amyloid Alzheimer's disease vaccine showed similarly promising results, but then caused worrisome side effects. Conducted in England, that human trial -- of an active peptide vaccine consisting of already-prepared amyloid-beta antibodies -- was halted in 2002 because 6 percent of participants developed encephalitis, a dangerous brain inflammation. Some participants also experienced brain shrinkage.

Hoping to avoid these side effects, University of Michigan researchers are experimenting with a modified version of the vaccine -- a "passive" form of immunization that induces the body to produce its own antibodies.

During the Japanese study, researchers found that long-term administration of DNA vaccines, which do not contain prepared antibodies, did not cause encephalitis. "In contrast to peptide vaccination, DNA vaccination induces low levels of antibodies for a relatively long period, so the immune-system stimulation is very mild," Matsumoto said. "This is very important to avoid the side effects such as encephalitis that developed after peptide vaccination."

Matsumoto is hopeful that DNA vaccines will someday be used to prevent Alzheimer's disease in high-risk patients and treat both early and advanced disease.

"In the early stage, we highly expect that DNA vaccination will prevent disease progression and, hopefully, normalize brain function," he said. "In advanced cases, however, neuronal loss and brain atrophy are very severe and irreversible. So it may be difficult to obtain clinical improvement with DNA vaccination."

Not all Alzheimer's disease vaccines in development are antibody-based. In 2005, researchers at Brigham and Women's Hospital in Boston released results of a study in which mice were treated with a nasal-spray vaccine containing Protollin and glatiramer acetate, medications that have been approved to treat conditions such as multiple sclerosis. The vaccine activates microglial cells, which gobble up amyloid-beta plaques. The Boston team found the vaccine reduced plaque accumulation in mice by 73 percent and did not cause encephalitis.

"Its mechanisms of action are different than those of our DNA vaccines," Matsumoto said. "However, in our unpublished data, we also observed the similar microglial activation after our DNA vaccinations. So the final step -- amyloid-beta reduction -- may be identical between this vaccine and our vaccines."

Dr. Sam Gandy, chairman of the Alzheimer's Association's Medical and Scientific Advisory Council, said, "Any of these vaccines could prove safe and effective. But we are years away from seeing them widely used in clinical practice -- but perhaps as few as three years away."

"The Japanese data points to a new strategy for vaccine delivery," Gandy said. "But we can't accurately predict which strategies will have which side effects. As the recent U.K. incident reveals, we are never certain until we test a vaccine in humans."

Gandy, who is director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia, added that anti-amyloid strategies are likely to have their greatest benefits as prophylactic treatments.

"Prevention may be more successful than treatment," he said. "We do not yet know how well the aged brain can recover from amyloid-induced damage."

More information

For more on Alzheimer's research, head to the Alzheimer's Association.

SOURCES: Yoh Matsumoto, M.D., department of molecular neuropathology, Tokyo Metropolitan Institute for Neuroscience, Japan; Sam Gandy, M.D., chairman, Medical and Scientific Advisory Council, Alzheimer's Association, Washington, D.C., also director, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia; June 12-16, 2006, Proceedings of the National Academy of Sciences
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