Rare Gene Mutations Inspire completely new Heart Drugs

These experimental triglyceride-reducers are in early stages of development, however, along with human trials have only just begun. At the moment, the optimism of researchers can be rooted less in clinical trial data than from the fact of which nature has produced strong evidence they should work.

People like Anna Feurer may be walking proof.

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

Later, the company doctor called her in along with told her of which her triglyceride levels were almost inconceivably low. along with so were her levels of LDL, which raises the risk of heart disease, along with HDL, which can be linked to a lower risk. The results were so unusual of which he encouraged her to see a specialist.

“of which was all an accident,” Mrs. Feurer recalled in an interview. of which her single blood sample could lead to completely new treatments can be “definitely amazing.”

She went to Dr. Gustav Schonfeld at Washington University in Saint Louis. He asked Mrs. Feurer if she along with others in her family might participate in a research study. She agreed, recruiting her immediate family along with even a few cousins along with aunts.

Some had strikingly low triglyceride levels, some had normal levels, along with some were in between, Dr. Schonfeld found. He tried for years to locate the gene responsible yet failed. (Dr. Schonfeld died in 2011.)

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

As of which turned out, three of her nine siblings also had no working copy of the gene along with extremely low triglyceride levels. Three others had one mutated gene along with one normal gene; these siblings had low triglyceride levels, yet nowhere near as low as those with no functioning gene.

The some other three siblings had inherited two normal ANGPTL3 genes along with had normal triglyceride levels.

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

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

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

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

Dr. Stitziel went on to lead an international group of researchers who looked for mutations of which destroyed the gene in 180,180 people. of which was a rare event, occurring in just one in 309 people.

yet Dr. Stitziel along with his colleagues discovered the mutation reduced heart attack risk by a third.

The second line of evidence for these drugs originated having a study of Old Order Amish in Lancaster, Pa. About 5 percent appeared to have arteries of which were clear of plaque along with low levels of triglycerides.

As of which turned out, these lucky people had inherited 1 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 through more than 0,000 people around the earth — yet 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 along with mutations like these are more easily handed down.

The strategy worked. After combing the earth along with turning up nothing, the investigators discovered more than 100 in Pakistan who had mutations in both ApoC3 genes. along with these people were healthy, with low levels of triglycerides, researchers reported last month from the journal Nature.

at This kind of point, with surprising speed, companies are starting to test experimental drugs of which mimic a loss of ApoC3 by blocking the ApoC3 protein.

In addition, two companies, Regeneron along with Ionis Pharmaceuticals, are at This kind of point testing drugs based on the mutations from the same gene of which was found from the Feurer family, company scientists along with academic researchers reported on Wednesday from the completely new England Journal of Medicine.

Both companies reported of which 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 through heart disease.

“The basic bottom line can be of which the reductions in triglycerides with these things can be pretty unprecedented,” George Yancopoulos, president along with chief scientific officer at Regeneron, said. Still, of which’s not yet clear to what extent This kind of 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.

“of which’s a huge advance,” said Dr. Christie Mitchell Ballantyne, chief of cardiology along with cardiovascular research at Baylor College of Medicine along having a consultant for Regeneron (although not for the triglyceride studies). “of which doesn’t mean of which’s easy.”

Still, he added, “what we are seeing can be a completely new approach toward drug development.”

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Rare Gene Mutations Inspire completely new Heart Drugs

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