A is for Alzheimer's disease.
B is for beta-amyloid, notorious as a hallmark _ or perhaps directcause _ of Alzheimer's.
C is for carbohydrates, one of amyloid's two key components.
In fact, one could go right on down the alphabet, past those ABCs, tolink amyloidosis with almost any number of other human diseases,hereditary and sporadic, benign and malignant, common and rare,afflicting young as well as old. High on the list: adult-onset diabetes,thyroid cancer, dialysis-induced joint disease, Mediterranean fever,spongiform encephalopathy (in humans and animals) and cardiacamyloidosis.
By now, researchers have identified more than 20 distinct amyloidproteins, each linked to a different disease. Prominent among theseamyloidologists is molecular pathologist Robert Kisilevsky, ofQueens University in Kingston, Ont.
He heads a multi-disciplinary team of Canadian scientists who havejust announced a first step toward fighting back against the proteanravages of amyloid deposition. Their article appears in the Feb. 1issue of Nature Medicine. Its title: "Arresting amyloidosis in vivousing small-molecule anionic sulphonates or sulphates: implicationsfor Alzheimer's disease."
Those implications, and Kisilevksy's research agenda, extendbeyond Alzheimer's disease to seek ways of thwarting amyloid'smultifarious role in other ailments, beginning with diabetes and heartdisease.
Needling The Body To Death
"Amyloids," Kisilevsky told BioWorld Today, "are tiny (7-10nanometers diameter) needle-like protein deposits that usually collectoutside of cells. They have very specific structural properties,depending upon how the protein has been folded up."
The very name `amyloid,'" he continued, "an old misnomer meaning`starch-like,' tells you that amyloid deposits involve a carbohydrateas well as a protein component. One of these," he continued, "theneedle-shaped fibrils are the proteins, each specific for a differentdisease. In the case of Alzheimer's, it's the beta protein, which formsthe characteristic plaques in the affected brain.
"A common denominator in amyloidosis," Kisilevksy said, "is thecarbohydrate element. By identifying when some of these commonelements are deposited," he explained, "we were trying to seewhether they might be involved in the genesis of amyloids. It turnsout that when the all-purpose carbohydrate component interacts withthe disease-specific component, it starts to confer upon that proteinthe kind of structural folding change that one sees under the electronmicroscope in Alzheimer's disease amyloid deposits."
That gave Kisilevksy and his team "the clue that maybe this wouldbe a useful target as potential therapy, because if we came up withmolecules that would interfere with this interaction, and therebyprevent the protein from taking on a conformation that one sees inamyloids, this might be a useful way of defining potentialchemotherapeutic agents."
In their Nature Medicine article, submitted last October, theCanadians reported on the anti-amyloid performance of elevenproprietary inhibitors. That number is now up to 40, and stillcounting.
To design these synthetic analogs, Kisilevksy said, "we obviouslytried to mimic the structure of the natural carbohydrate polymers,and that's how we hit upon the particular agents that turned out to beeffective in the animals."
Those in vivo murine models are mice in which an acuteinflammatory disease has been induced, marked by spleens swollenwith AA amyloid deposits. Cohorts of these animals then got one oranother of the 11 small-molecule inhibitors dissolved in theirdrinking water. A first group swallowed 20 micromolar quantities ofthe agent; a second, 50 mM. The third set of mice, now afflicted withsplenic amyloid, served as controls, drinking plain tap water.
Checking, Then Reversing, Disease Process
"A most striking effect," as the paper reported, "was seen withpoly(vinyl)sulphonate sodium salts (PVS) . . . whether given orallyor by intra-peritoneal injection, this agent, by comparison tountreated animals, virtually abolished splenic AA amyloid depositionfive days later."
At the same time, a test-tube experiment took on the amyloid betaprotein fibril assembly seen in Alzheimer's brains; it not onlychecked but reversed that disease process.
Co-author Paul Fraser, now at the University of Toronto, Kisilevskyrecounted, "was able to show that if he threw heparin sulphate into atest tube together with the beta protein at brain concentrations, healmost immediately got the beta protein fibrils. Then, when he addedsome of the compounds we've been working on he could get thoseneedles to unravel."
The proteins that go on to form amyloids, he pointed out, "arefrequently perfectly normal, but something happens during their lifespan to suddenly change the way they are folded up. And that'swhen pathology starts to occur."
Six Million Dollars To Reach Phase I
Two years ago, Queens University set up a wholly owned, privatebiotechnology company, Neurochem Inc., to license its growingportfolio of amyloid-inhibitor patents, and fund the team's furtherresearch.
For openers, two venture capital investors provided seed money inthe amount of Canadian $1 million. The firm's president and CEO,Joseph Curti, told BioWorld Today that about half this sum is still inthe bank. He now seeks Canadian $6 million to fund future researchand development through preclinicals into Phase I trials. "We are inactive negotiation," he said, "with five or six separate investors onboth sides of the border, and hope to get their final decisions by theend of February."
Curtis also is discussing collaborative agreements with "severalmultinational pharmaceutical companies."
Kisilevksy has a full agenda for spending the expected new financialinfusion: "The first thing we want to do," he said, "is sometoxicological studies, to make sure that our agents are not reallydamaging as far as living organisms are concerned. That's item one."
A second item is "doing some work in the future with a collaboratorto see whether the agents get across the blood-brain barrier, or howto try to modify them to get them to cross."
Once all of the above and other basic data are in hand, Kisilevskyconcluded, "At some point in the relatively near future we would liketo try to use our inhibitors in those forms of the amyloid that areaggressive and lead to rapid death. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.