BioWorld International Correspondent
LONDON - Hopes that there will one day be a safe and effective drug to treat Alzheimer's disease have been boosted by news of a compound that can strip a protein that plays a key role in the disease from the blood and tissues.
Researchers are about to test the compound on five people with Alzheimer's to check its safety and look for therapeutic effects. The drug, called CPHPC, already has been shown to be nontoxic in a larger trial where it was used to treat a different disease.
Mark Pepys, head of medicine at the Royal Free and University College Medical School in London, told BioWorld International: "There are several reasons why this discovery is scientifically very important and exciting. One is that this is a completely new mechanism of drug action. It is the first time that a small-molecule drug has been able to target a protein that contributes to a disease and completely remove it from the circulation."
In Alzheimer's disease, insoluble deposits of protein, called amyloid plaques, occur in the brain. Amyloid deposits can also occur in Type II diabetes, where they accumulate in the pancreas. In systemic amyloidosis, amyloid can build up in the major organs such as the heart, kidneys and liver. Although the severity varies, the condition kills about 1,000 people a year in the UK and more than 5,000 a year in the U.S.
The amyloid deposits that occur in those diseases all have one thing in common: They are covered by molecules of a protein called serum amyloid P, or SAP. That protein is found in the blood of healthy people but as soon as amyloid fibers appear, it sticks to them.
"It has always been a mystery why the body cannot get rid of amyloid when it forms," Pepys said. "Our past work has provided evidence that the coating of SAP protects the amyloid from being recognized and broken down, and this was why we were seeking a drug that would remove SAP from amyloid deposits."
Pepys, together with colleagues at the same institution and at Imperial College School of Medicine in London, the University of Southampton, Kumamoto University in Japan and F. Hoffmann-La Roche Ltd. in Basel, Switzerland, reports the culmination of the search in a paper in the May 16, 2002, issue of Nature titled "Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis."
Their search began in 1993, when Pepys and his team embarked on a drug discovery program in collaboration with Roche, whose chemists screened 100,000 compounds in an attempt to identify those that would stop SAP molecules from binding to amyloid fibers in the test tube. Out of four compounds that seemed to have some activity, one was more promising than the others.
A medicinal chemistry program began to modify the compound, and the result was CPHPC.
Preliminary tests of CPHPC in animal models where amyloid deposits occur were encouraging, and further experiments showed that the compound was completely nontoxic, Pepys said. At that point, Roche gave a license to Freemedic plc (the commercial exploitation arm of the Royal Free campus of the joint medical schools) to allow it to develop the drug commercially for applications other than treatment of Alzheimer's disease and Type II diabetes.
Pepys and his colleagues therefore decided to embark on a clinical trial of the drug in humans with systemic amyloidosis. "Results were very encouraging," Pepys said, "and most of the patients - for whom all other treatments had failed - remained clinically stable while they were taking the drug. In addition, during this trial we realized that not only did CPHPC remove SAP from amyloid deposits, it also - by gluing the SAP molecules together - tagged them for immediate destruction by the liver. As long as CPHPC was being taken, SAP levels remained very low."
The drug appears to mop up SAP from the blood, encouraging SAP present in the tissues out into the bloodstream, Pepys explained.
The team is now giving CPHPC to a larger group of patients with less severe systemic amyloidosis.
Participants in the pilot study of patients with moderate Alzheimer's disease will first be carefully assessed by cognitive testing, and have magnetic resonance imaging scans carried out to measure brain size. They also will be tested for various markers of the disease in the cerebrospinal fluid. After the period of treatment, all those parameters will be measured again in the hope of detecting whether cognitive decline or brain shrinkage has slowed.