Rare gene mutations inspire heart drug

What if you carried a genetic mutation that left you nearly impervious to heart disease? What if scientists could bottle that miracle and use it to treat everyone else?

In a series of studies, scientists have described two rare genetic mutations that reduce levels of triglycerides, a type of blood fat, far below normal. People carrying these genes seem invulnerable to heart disease, even if they have other risk factors.

Drugs that mimic the effects of these mutations are already on the way, and many experts believe that one day they will become the next blockbuster heart treatments. Tens of millions of Americans have elevated triglyceride levels. Large genetic studies have consistently suggested a direct link to heart disease.

Added to the existing arsenal of cholesterol-reducers and blood pressure medications, the new medications “will drive the final nail in the coffin of heart disease,” predicted John Kastelein, a professor of vascular medicine at the University of Amsterdam who was not involved in the new research.

These experimental triglyceride-reducers are in early stages of development, however, and human trials have only just begun. At the moment, the optimism of researchers is rooted less in clinical trial data than in the fact that nature has produced strong evidence they should work. People like Anna Feurer may be walking proof.

In 1994, Feurer, then 40, attended a health fair held by her employer, Ralston Purina, in St. Louis. She rolled up her sleeve and let a technician take blood to measure her cholesterol.

Later, the company doctor called her in and told her that her triglyceride levels were almost inconceivably low. And so were her levels of LDL, which raises the risk of heart disease, and HDL, which is linked to a lower risk. The results were so unusual that he encouraged her to see a specialist. “It was all an accident,” Feurer recalled in an interview. That her single blood sample could lead to new treatments is “definitely amazing.”

She went to Dr Gustav Schonfeld at Washington University in St. Louis. He asked Feurer if she and others in her family might participate in a research study. She agreed, recruiting her immediate family and even a few cousins and aunts. Some had strikingly low triglyceride levels, some had normal levels, and some were in between, Schonfeld found. He tried for years to locate the gene responsible but failed. (Schonfeld died in 2011.)

In 2009, he sent Feurer’s DNA to Dr Sekar Kathiresan, a cardiologist at Massachusetts General Hospital. He discovered that she carried mutations in both copies of a gene, ANGPTL3, involved in triglyceride metabolism. (Each individual carries two copies of a given gene, one from each parent.)

As it turned out, three of her nine siblings also had no working copy of the gene and extremely low triglyceride levels. Three others had one mutated gene and one normal gene; these siblings had low triglyceride levels, but nowhere near as low as those with no functioning gene. The other three siblings had inherited two normal ANGPTL3 genes and had normal triglyceride levels.

“The big question was, ‘Does this loss-of-function mutation reduce coronary risk’” Dr Daniel Rader of the University of Pennsylvania, who is an author of three of the recently published studies, said.

Dr Nathan O Stitziel, a cardiologist at Washington University in St. Louis, said the evidence so far was that people with Feurer’s mutation, at least, seemed to be protected.

Stitziel and his colleagues scanned Feurer’s coronary arteries and those of two siblings who also had two mutated ANGPTL3 genes. Each one was free of plaque, the researchers recently reported in the Journal of the American College of Cardiology.

One sibling had been a heavy smoker, had high blood pressure and even had Type 2 diabetes, a powerful risk factor for heart disease. Yet there was no plaque in his arteries.

Stitziel went on to lead an international group of researchers who looked for mutations that destroyed the gene in 180 people. It was a rare event, occurring in just one in 309 people. But Stitziel and his colleagues discovered the mutation reduced heart attack risk by a third.

The second line of evidence for these drugs originated with a study of Old Order Amish in Lancaster, Pennsylvania. About 5% appeared to have arteries that were clear of plaque and low levels of triglycerides. As it turned out, these lucky people had inherited a single mutated copy of another gene related to triglyceride production, called ApoC3.

Researchers wanted desperately to find people who had inherited two mutated copies to see whether short-circuiting the gene might be safe. They began by searching genetic data collected from more than 200,000 people around the world — but to no avail. Then the scientists tried a different tack, focusing on participants in a heart disease study in Pakistan, where first cousins often marry and mutations like these are more easily handed down.

Experimental drugs
The strategy worked. After combing the world and turning up nothing, the investigators discovered more than 100 in Pakistan who had mutations in both ApoC3 genes. And these people were healthy, with low levels of triglycerides, researchers reported last month in the journal Nature. Now, with surprising speed, companies are starting to test experimental drugs that mimic a loss of ApoC3 by blocking the ApoC3 protein.

In addition, two companies, Regeneron and Ionis Pharmaceuticals, are now testing drugs based on the mutations in the same gene that was found in the Feurer family, company scientists and academic researchers reported in The New England Journal of Medicine.

Both companies reported that in preliminary studies, drugs based on these mutations reduced triglycerides in people with elevated levels. Both also reported studies of the drugs in mice showing the drugs protected the animals from heart disease.

“The basic bottom line is that the reductions in triglycerides with these things is pretty unprecedented,” George Yancopoulos, president and chief scientific officer at Regeneron, said. Still, it’s not yet clear to what extent this will prevent heart attacks.

Even more significant may be the way in which these drugs were identified. Finding people who are impervious to a disease like heart disease can open a door to letting the rest of the population share their genetic luck.

“It’s a huge advance,” said Dr Christie Mitchell Ballantyne, chief of cardiology and cardiovascular research at Baylor College of Medicine and a consultant for Regeneron (although not for the triglyceride studies). “That doesn’t mean it’s easy.” Still, he added, “what we are seeing is a new approach toward drug development.”