By David N. Leff
You might suppose that Tangier disease (TD) is a North African ailment, named after the Moroccan city of Tangiers. In fact, TD owes its name to a small sandbank called Tangier Island in the middle of Chesapeake Bay.
Its 650 to 700 inhabitants make a living by catching crabs and oysters for the nation's seafood market, eked out by day-tripping tourists who come over from Virginia and Maryland, mainly for the sunsets and gift shops, according to local sources.
During the 1800s, the island suffered successive epidemics of cholera, tuberculosis, measles and smallpox. However, it was two small children, a boy of 5 and his 6-year-old sister, who, in the late 1950s, put Tangier Island on the medical map. It started with their tonsils.
"They had huge orange-yellow tonsils," recalled molecular geneticist Michael Hayden. "These were laden with cholesterol, as were their skin and cells, with lumps and bumps on their rectal mucosa, and enlarged liver and spleen. These children had almost no HDL [high-density lipoprotein]. So it was a dramatic representation that cholesterol couldn't get out of their cells at all."
So much so that the two pediatric Tangier Islanders were brought to the National Institutes of Health for workups, and their drastic symptoms given the name Tangier disease. Since then, some 40 cases of TD have made it into the literature, which makes it a very rare disease. In fact, the number of lipid-metabolism researchers far outnumbers that estimated TD population. The National Library of Medicine cites 305 articles on the subject since 1965.
But Hayden, a professor of medical genetics at the University of British Columbia in Vancouver, questions the rarity of TD. "There must be more patients than that," he told BioWorld Today. "We must have missed them." Hayden is senior author of a paper in the August 1999 issue of Nature Genetics, titled: "Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency."
It's widely known that cholesterol wears two hats, one white, one black. "LDL [low-density lipoprotein] is bad," Hayden explained, "because what happens is that LDL gets oxidized, and becomes injurious to the blood vessel wall. As a result it gets into the wall, sort of like a knife, and starts causing deposition of cholesterol just under the rim of the wall. That leads to obstruction of the vessel in areas where the lumen is not very large - particularly the coronary arteries."
The Good, The Bad, And The Artery
"So LDL is in a constant battle to enter and injure the vessel wall," he continued. "But one of the battles that it fights is against HDL. As LDL is pushing the vessel wall in, HDL is bringing it out. So the battle is between the good and bad cholesterol.
"And you can get coronary artery disease," Hayden pointed out, "either because of too much LDL, or because of too little HDL. And it happens that too little HDL is the commonest lipid abnormality in patients with heart attacks and strokes - more common than elevated LDL."
Cardiovascular disease is usually cited as the number one cause of morbidity and mortality in the Western world, with more than 950,000 deaths annually in the U.S. alone. "It used to be in the more industrialized countries," Hayden observed. "Now it's everywhere, including the developing countries."
Sales of drugs that lower "bad" LDL cholesterol total $8 billion to $10 billion a year. But there is no effective treatment on the market to raise low levels of "good" HDL cholesterol. "The statins do that to a marginal degree - 5, 7, 8 percent," he said. "We need something that does it 30 or 40 percent.
"We do know that if you raise HDL levels significantly," Hayden went on, "you can overcome even the effect of an increased 'bad' LDL cholesterol. So we have been essentially fighting the battle of atherosclerosis with very few soldiers, and only one arm. We've done well, but the opportunity to think about ways to raise HDL cholesterol gives one the opportunity to have a more dramatic effect on the frequency of cardiovascular disease."
By conducting genetic linkage analysis of large families with inherited familial HDL deficiency, plus two TD patients, Hayden and his co-authors discovered that a single gene, ABC1, on the long arm of chromosome 9, is responsible for both diseases. "Mutations are scattered throughout the gene," he observed, "not localized in one region. There wasn't a single family whose members had the same mutation. They all had different mutations. And they're very different: Some are deletions, some missense mutations, truncations where the gene is stopped, so there's a whole host of different mutations underlying this phenotype."
Of their two TD probands, Hayden recounted, "One was Dutch, the other of English descent. Importantly, the latter was consanguinous, the offspring of a first-cousin mating. That helped us a lot. It told us that in all likelihood the mutation should be the same on both chromosomes in both parental genes."
Looking For A Few Good Firms
Hayden is chief scientific officer of Vancouver-based Xenon Bioresearch Inc., which co-authored the Nature Genetics paper. "The key medium-term goal," he concluded, "and here we're working with Xenon, is to identify potential compounds that could be used - employing the activity of this gene and its exprressed protein - in an assay to identify compounds that have the potential to raise HDL levels in humans."
Xenon's president and CEO, Frank Holler, observed, "Now what we really have to do is understand the mechanism for reverse cholesterol transport, and develop drugs that will block or otherwise modulate that pathway. So our strategy," he told BioWorld Today, "is to develop the assays of that drug target, to allow us to screen for small-molecule compounds. Xenon has made remarkable progress toward that goal with the resources that we've had, but certainly we're looking for the additional resources that a partnership can bring. We're discussing the program with a combination of pharma and tier-one biotech companies that have shown an interest at this time."