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HEART Disease

The Milano Defense

A Chance Mutation Gave One Man and His Descendants the Ability to Withstand the Ravages of Cholesterol Buildup. New Research Shows It May Be Possible Through Gene Therapy to Give Others the Same Benefits.

August 22, 1996|Marnell Jameson | Special to The Times

Usually, genetic mutations mean bad news. But in the case of Giovanni Pomaroli, his defective gene spawned a lineage that appears invincible to the ravages of heart and vascular disease and may hold a clue to preventing the scourge in others.

A chance genetic mutation endowed Pomaroli, who was born in the remote town of Limone, Italy, in 1780, with an unusual protein that prevented cholesterol from building up in his arteries. It allowed him and his descendants to eat massive quantities of fatty foods, smoke to excess, avoid exercise and still live well into their 90s.

Now a research team at Cedars-Sinai Medical Center in Los Angeles is using the protein from this mutant gene to prevent cholesterol buildup in the arteries of rabbits and mice that were not naturally endowed with it. Perhaps as early as next year, they will try to do the same in humans.

If all goes well, among the first people who could benefit are those who have vascular disease but are not candidates for surgery or angioplasty. Another group would be those who have trouble lowering their cholesterol levels through diet and medication. Patients who have undergone angioplasty to clear their arteries might receive it to prevent further clogging.

FOR THE RECORD - CLARIFICATION
Los Angeles Times Thursday August 29, 1996 Home Edition Metro Part B Page 2 Metro Desk 2 inches; 40 words Type of Material: Correction
In last week's Science File, a photo caption affiliated Dr. Prediman K. Shah with UCLA. Dr. Shah is affiliated with both UCLA and Cedars-Sinai Medical Center in Los Angeles, as the story stated. The story also stated correctly that the genetic research project was performed at Cedars.

"We are on the trail of something that could substantially impact vascular disease," said UCLA's Dr. Prediman K. Shah, director of cardiology at Cedars-Sinai and principal investigator on the study.

However, Dr. Jon Kobashigawa, medical director of UCLA's heart transplant program, is concerned that injecting the mutant protein into humans might produce unexpected side effects or that recipients will produce antibodies against the protein that will quickly nullify its effects. "Very small changes in molecules can trigger a whole cascade of reactions in the body that may not be too desirable," he said.

Apo A-1 Milano, the protein created by the aberrant gene, was discovered in Pomaroli's descendants in 1980 by Cesare Sirtori of the University of Milan, who was treating one descendant for a stomach problem when he noted the discrepancy between the man's horrible eating and smoking habits and his remarkably clear arteries. The mutant gene was eventually isolated and produced in relatively large quantities by researchers at Pharmacia AB, the Swedish drug company that now supplies it to researchers.

Apo A-1 Milano is, in a sense, a biological garbage truck that removes cholesterol from the arteries and dumps it in the body's waste stream.

Humans have three types of cholesterol in their blood--the so-called "good cholesterol" (high density lipoprotein, or HDL), "bad cholesterol" (low-density lipoprotein, or LDL) and triglycerides.

LDL carries cholesterol through the body, but it tends to fall apart, leaving plaque deposits on the walls of blood vessels. Triglycerides are converted into LDL. HDL, in contrast, binds cholesterol tightly and carries it to the liver for disposal.

Apo A-1 is a key building block of HDL, and the Milano variant seems to make it work better, said Dr. Jack Oram of the University of Washington School of Medicine.

In Shah's first study, the team fed rats a high-fat diet and scratched the insides of some arteries, a technique that accelerates the formation of atherosclerotic plaque. After plaque built up, the researchers performed angioplasty, in which a balloon is inserted and inflated to compress the plaque. Half the animals received an injection of the Apo A-1 Milano protein before and after angioplasty.

When the team examined both groups three weeks later, they reported in 1994, they found that rabbits that received the mutant protein had 70% less thickening of the artery wall from plaque buildup. Sirtori has reported similar results.

In their latest study, Shah's group set out to see whether they could reproduce the results in mice, and more important, to see whether they could reverse plaque that had formed. This study used a type of mouse whose arterial disease closely resembled that in humans.

"The results are pretty spectacular," said Shah, who plans to publish the findings this year.

At the end of the five-week study, mice receiving a low dose of Apo A-1 Milano had 60% less plaque than the control group. In those mice receiving a high dose, plaque was reversed by nearly 80%. Furthermore, in the plaque that remained, the fat was virtually nonexistent.

In the coming year, Shah's team hopes to determine the lowest dose needed to be effective, how long the protein has to be administered, whether the body develops antibodies against it and whether the effects are permanent.

"We have proven the concept," Shah said. "The gene does protect rabbits and mice by both preventing the formation of fatty plaque and also reversing plaque once it's formed."

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