Heart disease is the leading cause of death in the United States, and high cholesterol is a major indicator of risk. Some lucky people are protected by a genetic aberration that naturally lowers their cholesterol levels. Now several companies are pursuing drugs that mimic this genetic quirk—hoping that it might help reduce the artery-clogging lipid. If successful, the new cholesterol therapy could be an example of the power of using human genetic discoveries in drug development.

Low-density lipoprotein (LDL) cholesterol, or “bad cholesterol,” is directly correlated to heart disease. Drugs known as statins, such as Crestor and Lipitor, lower LDL cholesterol by inhibiting an enzyme that plays a role in its production, and these are some of the most widely prescribed drugs on the market in the U.S. But clinical trials suggest that genetically inspired drugs could lower LDL-cholesterol levels even further, and could especially benefit patients who can’t tolerate statins.

At the American Heart Association meeting last month, the drug companies Amgen and Pfizer both reported promising signs from mid-stage clinical trials of two such drugs, which target a gene known as PCSK9.

The role of PCSK9 in heart health was uncovered by a 2006 human genetics study of people who had lower-than-average amounts of LDL cholesterol in their blood and greatly reduced incidence of heart attacks and other cardiac complications. The cause was identified as faulty copies of the PCSK9 gene. The protein product of this gene regulates LDL cholesterol levels in the blood by decreasing the quantity of a receptor that pulls LDL cholesterol out of the blood.

A third company, Alnylam, a biotech focused on RNA-interference-based treatments, is also running early-stage trials of a PCSK9 gene-silencing treatment (see “RNA-based Cholesterol Drug Is Readied for Human Tests”). And a fourth company, Regeneron, seems to have the lead, having already begun late-stage testing of its PCSK9 inhibitor.

Bill Sasiela, director of the PCSK9 program at Regeneron, says that PCSK9 moderates the activity of LDL receptors by tagging them for destruction. So when the level of the PCSK9 protein is low, there are more LDL receptors around to remove LDL cholesterol from the blood.

To try to replicate this situation for patients with naturally high levels of cholesterol, Sasiela and his team are developing an antibody-based therapeutic, which binds to the PCSK9 protein and blocks it from interacting with the LDL receptor.

Regeneron has been able to move into human testing unusually quickly thanks to its genetic technology, which includes a special strain of transgenic mice. By replacing large pieces of the mouse genome with human versions, the company has created mice that produce more-or-less human antibodies. The antibodies are not seen as dangerous by the immune system of patients and are not destroyed.

The PCSK9 gene was first identified in 2003, says Sasiela, and the time frame of moving from a basic discovery to late-stage clinical trials in less than 10 years is “amazingly short.” In the future, he expects human genetics to continue driving drug development. “That what is going to be generating our new targets in therapy,” he says.