A defective gene that actually confers a benefit—protection against atherosclerotic heart disease—has inspired a new therapeutic strategy: replicate the defective gene’s loss-of-function consequences by administering a drug that antagonizes the “healthy” gene’s product. This strategy, put to the test by researchers based at the University of Pennsylvania, has succeeded in lowering blood lipids and decreasing the odds of atherosclerotic heart disease.

The gene in question is called ANGPTL3. It regulates enzymes that clear triglycerides and other fat molecules from the blood. Research in recent years has hinted that inherited mutations in the ANGPTL3 gene that disable its function can decrease triglyceride, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels.

The drug administered by the researchers is called evinacumab, an investigative injectable monocloncal antibody. According to the researchers, evinacumab reduced triglycerides by up to 76% and lowered LDL-C 23% in human study participants, and largely reversed signs of atherosclerosis in a mouse models.

Additional details appeared May 24 in the New England Journal of Medicine, in an article entitled, “Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.” The article, contributed by researchers from Penn Medicine, Regeneron Pharmaceuticals, and a group of international collaborators, not only evaluated the effects of pharmacologic antagonism of ANGPTL3 with a human monoclonal antibody, it also examined the relationship between ANGPTL3 loss-of-function variants and coronary artery disease in a large number of participants sampled from a large U.S. healthcare system, with follow-up studies in four population cohorts.

To investigate the relationship between ANGPTL3 variants and coronary artery disease, the researchers considered data from approximately 188,000 people and found that carriers of mutations that disable ANGPTL3 had nearly 40% fewer incidents of coronary artery disease as compared to those with fully functioning ANGPTL3.

“In the clinic, I treat many patients with very high triglycerides, but our current medications aren't lowering triglycerides enough in many cases. I'm delighted at the prospect of a new treatment that's a lot more potent, all the more because it lowers LDL at the same time,” said study co-author Richard L. Dunbar, M.D., assistant professor of Cardiovascular Medicine and member of Penn's Division of Translational Medicine and Human Genetics. “It's very reassuring to see that people with this genetic defect actually seem to be protected from heart disease. I think that really bodes well for a therapeutic that's targeting the ANGPTL3 pathway.”

In a separate study, published in the April issue of the Journal of the American College of Cardiology (JACC), researchers from Penn Medicine, Harvard Medical School, Washington University in St. Louis, and nine other institutions, who also studied humans and mice, reported on a similar set of findings. Among these was the discovery from another large population sample that carriers of ANGPTL3-inactivating mutations had a 34% lower rate of coronary artery disease compared to non-carriers.

“We used different lines of evidence to show that ANGPTL3 deficiency is associated with a reduced risk of coronary artery disease,” said study co-author Kiran Musunuru, M.D., Ph.D., an associate professor of Cardiovascular Medicine at Penn. “But ultimately we were able to identify that fact that carriers of this genetic mutation did in fact experience a benefit—with little other health risk.”

The trial of research on ANGPTL3 as a potential target for atherosclerosis prevention began over a decade ago when scientists reported on two cases of familial hypolipidemia, a rare inherited condition involving abnormally low blood levels of cholesterol and triglycerides. Most cases of familial hypolipidemia are linked to other gene mutations that cause liver and digestive problems, but in members of this American family with the condition, Dr. Musunuru found mutations in the gene for ANGPTL3, and no associated health problems.

In the NEJM study from Dunbar and colleagues, the antibody had similar effects in an initial clinical trial in 83 people, lowering the blood levels of triglycerides measured after fasting by about 75% at the highest dose, and lowering LDL-C by about 30%.

Statins and other drugs are already widely used to lower LDL-C, but there are fewer options for lowering triglycerides. “For treating high triglyceride levels there's really nothing out there that's quite this potent, so that's where I expect this new approach to have its greatest therapeutic benefit,” Dr. Dunbar said.

Hypertriglyceridemia, a condition in which fasting triglyceride levels are greater than 150 mg/dL, is estimated to affect at least tens of millions of American adults. It is associated with coronary artery disease and other forms of atherosclerosis, and can lead to potentially fatal inflammation of the pancreas.

In principle, the strategy of targeting ANGPTL3 could have an even broader use in treating atherosclerosis in the general population. The researchers found that in a mouse model of atherosclerosis, treatment with evinacumab reduced the area of atherosclerotic lesions by 39%.

“These results mirror the reduction in plasma lipid levels and atherosclerosis progression that we observed in dyslipidemic mice treated with evinacumab, a human monoclonal antibody inhibitor of ANGPTL3,” the authors of the NEJM article noted. “Our results provide evidence that the combined hypolipidemia profile associated with genetic or therapeutic antagonism of ANGPTL3, which includes a reduction in levels of HDL-C in addition to LDL-C and triglycerides, is antiatherogenic.”

Population study findings for the NEJM and JACC studies suggest that even the partial inactivation of ANGPTL3—carriers typically have one mutant copy of the gene and one working copy–may be powerfully protective against coronary artery disease, which has long been one of the leading causes of death in developed countries. In the JACC study, for example, carriers of inactivating ANGPTL3 mutations had only a 17% reduction in triglycerides on average. But that modest reduction was associated with a 34% reduction in coronary artery disease risk. Moreover, Dr. Musunuru and his colleagues found that the people in their sample with the lowest blood levels of ANGPTL3 had a 35% lower rate of heart attacks compared to those with the highest ANGPTL3 levels.

Dr. Dunbar noted that the population study findings probably have laid to rest a lingering concern about targeting ANGPTL3, namely its effect in lowering not just LDL and triglycerides but also the so-called “good cholesterol,” known as HDL-C. “If lowering HDL were a major concern, then I don't think we would have seen the evidence of overall benefit that we did in this study,” he said.

The two studies together suggest that single copies of inactivating ANGPTL3 mutations are found in roughly one of every 250 people of European descent, whereas people with mutations in both copies of the gene—as in the family studied by Dr. Musunuru and colleagues—are much rarer.

According to Dr. Dunbar, the next logical step would be to take evinacumab into larger clinical trials to study its safety, effectiveness, and optimal dosing. “The effect of even a single dose lasts for several months, and it's plausible that with multiple doses we would see an even deeper and more sustained effect,” he said.

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