By disabling a dementia-linked protein, a synthetic drug is showing a tantalizing capacity to interfere with the formation of waxy amyloid deposits like those that accumulate in the brains of people with Alzheimer’s disease.
In those people, the protein, serum amyloid P, seems to exacerbate the buildup by linking amyloid molecules into more durable deposits. Research hasn’t revealed whether these deposits cause Alzheimer’s disease or are the result of it, but many scientists argue that limiting amyloid deposits will benefit patients (SN: 11/3/01, p. 286: Available to subscribers at Attacking Alzheimer’s.).
Immunologist Mark B. Pepys of the Royal Free and University College Medical School in London and his colleagues report taking a step in that direction. In the May 16 Nature, they show that a drug called CPHPC can reduce the amount of serum amyloid P in the blood and in amyloid deposits. CPHPC is merciful shorthand for R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2-carboxylic acid.
The drug works by binding to serum amyloid P, which then can’t bind to amyloid molecules. Further, like its abbreviation, the structure of CPHPC is palindromic–it looks the same from either end. With its two binding sites, the drug can hold together two serum amyloid P molecules.
Liver cells then recognize the structure and mark it for destruction.
The researchers developed CPHPC by first searching a collection of roughly 100,000 compounds for molecules that interact with serum amyloid P. The team chemically modified one promising candidate so that it would bond decisively to serum amyloid P. The drug candidate, CPHPC, did just that in test-tube and mouse studies. In mice genetically engineered to make human serum amyloid P, CPHPC lowered the concentration of serum amyloid P in the blood and shrank amyloid deposits.
The researchers then gave 2-day CPHPC infusions to eight people with amyloidosis, a life-threatening disease in which amyloid deposits accumulate not in the brain but in the kidneys, liver, heart, and other organs.
The body normally maintains a uniform concentration of serum amyloid P in the blood. In the study volunteers, the CPHPC infusion depleted the blood’s supply of serum amyloid P, so the protein was drawn out of the organs. When treatment ended, the serum amyloid P started to go back into the organ deposits. However, several weeks after the treatment, some patients still had less serum amyloid P in both their blood and amyloid deposits than they had when the study began.
In another trial, the teams gave up to 9 months’ of daily doses of CPHPC to 19 amyloidosis patients whose disease was progressing despite other treatments. An autopsy on one patient who died 6 months into the treatment showed that his amyloid deposits were surprisingly low in serum amyloid P.
This study revealed no side effects. Although the researchers haven’t yet tested whether the treatment broke up amyloid deposits, most of the patients’ conditions stabilized. Stopping the disease progression “is better than nothing,” says immunologist Carolyn Mold of the University of New Mexico School of Medicine in Albuquerque.
In that sense, she says, CPHPC represents “an exciting possibility” that deserves further testing.
Pepys and his colleagues plan to begin testing the drug on Alzheimer’s patients soon. Although the researchers have great hopes for CPHPC, Pepys cautions that all testing is still in the early phase and that there are significant differences between Alzheimer’s disease and amyloidosis.