Trial Drug May Help Treat Alzheimer's
Interferes with a molecule that protects plaques
WEDNESDAY, May 15, 2002 (HealthDayNews) -- An experimental drug may prove a novel treatment for Alzheimer's disease and other disorders marked by the abnormal buildup of proteins.
The drug, CPHPC, interferes with a molecule called SAP -- short for serum amyloid P component -- that seems to provide critical cover for the plaques that accompany Alzheimer's and various other protein-folding disorders. In both mice and people, British scientists have shown the drug cleared SAP from the blood and from amyloid deposits throughout the body.
Whether doing so can reduce the burden of plaques in the brain and other organs remains uncertain. The researchers are beginning a study to test their drug in people with Alzheimer's, although they don't expect at this stage to see a reversal in plaque buildup. A report on their progress appears in tomorrow's issue of Nature.
While Alzheimer's disease is believed to be caused by plaque accumulation in the brain, no treatment is available yet that reverses this process.
The trial of a vaccine that turns the immune system against amyloid plaques was suspended earlier this year after many patients developed serious brain inflammation. However, animal experiments that paved the way for the human study showed the vaccine did reduce plaques and improve brain function.
"We do know that the amyloid deposits are in a state of dynamic turnover," says lead author Dr. Mark Pepys, of Royal Free and University College Medical School in London. "If you prevent new plaques from forming, they regress in about half the patients. We know it can be broken down [by the body], but it's broken down rather slowly. But it won't break down if there's more being formed."
Enter SAP. The protein's main job is to scavenge for disintegrating genetic material disgorged from dead cells. Without it, the body might perceive the DNA fragments as hostile and launch a disastrous immune reaction against the molecule.
Over the last two decades, Pepys and his colleagues have learned that SAP plays an important role in plaque disorders, too. It binds to plaques -- themselves abnormally folded proteins clumped into fibers -- preventing them from being broken down.
"We believe it stabilizes them and masks the fibers" from agents that would normally dissolve them, he says. SAP itself is also quite resistant to breakdown, and may have a sort of protective cocoon that gives plaques an extra measure of defense.
To develop their drug, Pepys' team first screened a fleet of chemicals to see which blocked the binding of SAP. They hit on CHPCP, a small molecule that doesn't get absorbed by the body.
Yet as it circulates through the bloodstream, Pepys says, CHPCP "does this extremely clever trick." Finding free SAP proteins, it strings them together in such a way that they get shuttled to the liver and destroyed. The drug then either leaves the body or finds another pair of SAP molecules to unite.
In mice, SAP is essentially eliminated from blood within a day of administering CHPCP. However, once treatment is stopped the proteins return.
Pepys' group has now given infusions or injections of the drug to 19 people with amyloid plaque disorders -- causing deposits in organs like the liver and spleen -- for an average of 2.6 months and up to 9.5 months.
The therapy drove blood levels of SAP to roughly 5 percent of its pre-treatment mark. And while many of the patients were terminally ill and took the experimental drug as a last-ditch hope, most saw their symptoms stay stable as long as they were receiving treatment.
Pepys and his colleagues now plan to test the drug in five to 10 people with moderate to severe Alzheimer's disease. They want to see how well it's tolerated, and, optimistically, whether it might slow the progression of their illness.
Ultimately, Pepys hopes to develop an oral form of CPHPC to avoid the need for injections.
Because of its work as a DNA scavenger, Pepys says CPHPC in theory could make patients vulnerable to an autoimmune attack.
"I'm reasonably confident that won't happen," he adds, noting there have been no side effects from the drug in any of the people who've taken it so far.
Dr. Joel Buxbaum, an amyloid plaque expert at the Scripps Research Institute in La Jolla, Calif., calls the latest study "a really nice piece of work," and praises the researchers' approach.
However, Buxbaum warns against making too great a leap from the findings. One major question mark, he says, was whether breaking up amyloid fibrils is in fact a sound tactic. Some evidence, including his work, suggests plaques are less toxic in this form and that when dispersed cause cell damage and death.
"It's an open question," he says.
What To Do: For more on Alzheimer's disease, try the Alzheimer's Association. To learn more about protein folding and why it's important, try the National Institutes of Health or the University of Pennsylvania.