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Italian Gene Holds Hope for Unclogging Arteries : Medicine: A mutant protein found in one family appears to ward off heart disease despite a high-fat diet. Researchers buoyed by animal trials.

October 17, 1994|From Associated Press

Cristoforo Pomaroli and Rosa Giovanelli had a son in 1780 in their small town in Italy, never knowing they bequeathed a genetic legacy that offers hope for reversing heart disease two centuries later.

The boy's descendants in the northern Italian town of Limone inherited a genetic defect that protects them from the scourge of Western living--fatty deposits that clog the arteries.

The 38 lucky carriers have a simple mutation in a protein of so-called good cholesterol that lets them eat red meat, sausage and butter without artery-clogging deposits.

They range in age from the teens to nearly 90. And they have never worried about strokes or heart attacks since longevity runs in the family.

"They are almost all smokers. They eat like hell, the worst diet," said the University of Milan's Dr. Cesare Sirtori, who screened residents of Limone for the miracle mutation.

Ever since Sirtori discovered the mutation, called Apolipoprotein A-1 Milano for the university where he is a pharmacology professor, doctors have wondered about harnessing its power to eliminate coronary artery disease.

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"Eventually it is not inconceivable that the gene could be transferred to the liver or other organs of very high-risk people who could then end up manufacturing it on their own," said Dr. Prediman K. Shah, director of the cardiac care unit at Cedars-Sinai Medical Center.

Shah leads a U.S.-Swedish team examining the more immediate potential to reduce the deadly reclogging that occurs after a blocked vessel has been cleared with balloon angioplasty surgery.

In the October issue of the American Heart Assn. journal Circulation, Shah reports that injections of a genetically engineered version of the protein dramatically reduced the reclogging of rabbits' coronary arteries.

Before and after surgery, eight rabbits got injections of Apo Milano attached to a fat molecule that targets the proper site. Eight others got injections of only the fat molecule. Four rabbits got no treatment.

"The striking finding was in the rabbits that received the recombinant version of the Apo Milano; the amount of plaque that built up was 70% less than the (untreated) control group," Shah said.

Sirtori said he will publish similar results in December showing "no plaque at all" in rabbits injected with Apo Milano. Shah said he will test monkeys, pigs and mice before considering human trials, a point that could take several years to reach.

Shah learned about the Limone mutation two years ago while searching for sources of synthetic high-density lipoprotein, HDL, which is cholesterol that might reduce reclogging.

He read that Sirtori stumbled upon a strange form of HDL in 1974 while examining a man with sky-high levels of cholesterol and triglycerides but no coronary artery disease. Somehow good cholesterol was keeping the bad from wreaking havoc. Through records in Limone, Sirtori traced the anomaly to Pomaroli and Giovanelli, then went to the town and screened every resident older than 10.

"I believed it was something important. I mailed samples all over Europe to colleagues. Nobody gave a damn about it," Sirtori said from Milan.

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Eventually, the Swedish biotechnology firm Pharmacia A.B. began producing the laboratory version, supplying Shah and co-investigators at the Karolinska Institute in Stockholm.

Lars O. Andersson, Pharmacia's director of cardiovascular research, said the company is gambling on Apo Milano.

"We hope to be able to introduce a treatment to give once a week for somewhere from two to six months, and that treatment would induce regression of atherosclerosis," the common form of artery buildup, Andersson said from Stockholm. "If it works, it would be revolutionary."

The animal studies drew cautious reactions.

Dr. James Willerson, editor of Circulation and medical director of the Texas Heart Institute in Houston, called the results "very interesting." He added: "I learned long ago not to get too excited about an observation made in animal models until one can show it works and is safe in humans."

Dr. Antonio Gotto, past president of the American Heart Assn., sees only limited applications "after angioplasty or bypass surgery to keep the arteries or grafts open."

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