By David N. Leff

Shortly after Election Day last month, a prominent political personality - vice-presidential candidate Richard Cheney - underwent a cardiovascular procedure that involved angioplasty and implanting a steel-mesh stent in a coronary artery. Its purpose: to forestall restenosis - re-blockage of the blood vessel. It happens in 20 to 30 percent of patients.

"If you look at Cheney's history," said research immunologist Kenneth Kornman, "it's not a very favorable history. Certainly this is an individual who has had multiple cardiac procedures at a relatively young age, and quite frankly, he's got a lot of additional risk factors out there. He's under at least moderate stress, probably not eating very well, and the guy doesn't exercise very much. So this is an individual who certainly highlights the issues in terms of recurrent cardiovascular disease and potential problems with stents."

Kornman is chief scientific officer of Interleukin Genetics Inc.(IGI), in Waltham, Mass. The company's scientific collaborators in Europe are co-authors of a paper in the Journal of the American College of Cardiology, December 2000 issue. Its title: "Protective role against restenosis from an Interleukin-1 receptor antagonist gene polymorphism in patients treated with coronary stenting."

"Interleukin-1 [IL-1]," Kornman told BioWorld Today, "is a molecule of the immune system that is switched on whenever there is any trauma or outside challenge or stress to the body. First of all it regulates inflammation and wound healing."

It's Some Genes - Not All - That Do It

"Restenosis," he said, "is an aberrant form of wound healing. It involves excessive growth of certain types of tissue in a somewhat uncoordinated manner. So what we believe is happening is that these IL-1 polymorphisms are altering those wound-healing cascades that occur when surgeons go in and repair these atherosclerotic lesions by placing these stents. So the net result is either a favorable wound-healing response or a somewhat uncoordinated one." (See BioWorld Today, Nov. 9, 2000.)

The journal paper reported on a clinical trial of 1,850 consecutive patients at the Technical University of Munich's Heart Center, in Germany, who underwent angioplasty and stent placement. Six months later, the paper reported, those patients who carried a not-uncommon variation in their IL-1 receptor antagonist gene had a 22 percent lower risk of restenosis than those who lacked the variation. Among subjects under 60 years of age, this risk was even lower - 37 percent.

The interleukin-1 receptor antagonist gene, which sits on a 430-kilobase stretch of human chromosome 2, "encodes a protein that suppresses inflammation by blocking the action of IL1," Kornman noted. He said his company has filed a patent application on the correlation of this DNA variation and the risk of restenosis.

"In current clinical practice," he said, "the likelihood of restenosis occurring is unpredictable. When it does happen, the usual revascularization options are bypass surgery or a second angioplasty."

As for potential drug therapy, he added, "There are several major drug development efforts that have been less than encouraging in clinical trials. Part of that relates to the lack of clarity on the genetic mechanism why this occurs in some people and not in others. So one of the potential opportunities here, as seen from the paper, is that the IL-1 genotype may point to some major mechanisms that give this opportunity from a drug development standpoint."

Perhaps most importantly, Kornman added, "we believe it will help to identify high-risk populations that may be ideal for testing some of the drugs that may already exist. What the pharmaceutical companies have done - very logically, I think - is look at various drugs that already exist - already gone through safety testing and approval for other indications - that may fit into the restenosis mechanism. Things as simple as statin drugs for regulating lipid. And they say, 'Okay, maybe this is a lipid phenomenon. Let's test statins to prevent restenosis.'"

Kornman sees a future for the Interleukin-1 receptor antagonist gene variation in predictive testing for restenosis risk. "To us," he said, "this is a situation where you have a high-cost, high-consequence medical condition that occurs in a relatively short period of time. You know it when it happens. A person has recurrent symptoms in the first year after stent placement. Is that individual at high risk? Currently there's no way to identify up front who that individual is going to be.

"Right now, there's nothing we can do about it, but there are some drugs that look promising," he said. "Their clinical trials just haven't been definitive. I think the opportunity for our company is to link some drugs up with the high-risk individuals, and see if we can find a way to prevent this high-consequence outcome."

Foreseeing Restenosis By Genetic Testing

"This may be a very good situation medically for using genetic tests in a predictive manner to guide drug therapy," Kornman suggested. "And it's very different from the way genetic tests are currently being used. It fits more with the long-term vision of how such testing will fit into a predictive-medicine mode."

Routine genotyping of all candidate cardiovascular patients, he said, "is a not-unlikely scenario. Revascularization is a very high-cost procedure, and right now, even with stents you're looking at a substantial number of people - at least 20 percent on a nationwide basis - who still have restenosis complications. So if there was a way to run a test that might cost $120 or $150 that would identify individuals at higher risk - twofold risk, for example - who should be on a specific medication for six weeks following the stent placement, that sounds like a pretty good way to go."

Kornman said IGI is "just now starting to talk with potential partners who have some of these drugs that are being tested for restenosis. We're discussing the opportunity for genotyping some of their populations that have already been studied to see if we can find some IL-1 genotype-drug interactions in terms of restenosis prevention."

IGI's CEO, Philip Reilly, added, "These results bring us closer to our goal of providing the medical community with an important new, low-cost, DNA-based assessment tool to evaluate patients prior to elective angioplasty, as well as to tailor their clinical follow-up to their risk of restenosis."