An unorthodox way to lower “bad” cholesterol by suppressing a liver protein may soon challenge statins for the cholesterol-drug crown.

Suppressing the protein’s activity in rats and macaque monkeys lowered the animals’ bad cholesterol by 50 to 70 percent, researchers report online and in an upcoming Proceedings of the National Academy of Sciences.

“This is the first study to show that you can acutely lower ... cholesterol levels in several animal species” using a process called RNA interference, says study coauthor Kevin Fitzgerald, director of research at Alnylam Pharmaceuticals in Cambridge, Mass.

RNA interference has become a hot area of drug development research. By injecting short RNA molecules only 20 to 25 “letters” of genetic code long into patients, scientists can selectively suppress the activity of a disease-related gene that has a matching segment of genetic code.

In this case, Fitzgerald and his colleagues designed the RNA to suppress the gene that encodes PCSK9, a protein that helps regulate LDL, the bad cholesterol. High LDL cholesterol in the blood increases people’s risk of heart disease.

The new research “gives the proof of concept that if you decrease the level of PCSK9, you can truly affect the level of cholesterol,” comments Catherine Boileau, a geneticist specializing in inherited cholesterol disorders at INSERM, the French national health institute.

This new RNA interference–based approach could provide an alternative to statins, a widely used family of cholesterol-lowering drugs. “The problem with statin therapy is that not all people are good responders to the treatment,” Boileau says. “There’s a need for new cholesterol lowering agents.”

PCSK9 normally reduces the amount of cholesterol that cells can absorb from the bloodstream, so suppressing the protein boosted cells’ absorption. As a result, the treatment lowered bad blood cholesterol levels about as much as a high dose of statins. The reduction lasted about three weeks, and HDL, the good cholesterol, was not affected.

To deliver the RNA molecules into cells, Fitzgerald’s team packaged the molecules in microscopic spheres of fat called lipidoid nanoparticles. Because blood vessels in the liver are more porous than elsewhere in the body, the RNA-carrying nanoparticles could more easily pass out of those blood vessels and into the liver, which regulates cholesterol.

“I would say it’s promising if we can specifically target the [RNA] to the liver,” Boileau says. Suppressing PCSK9 in other organs could have unwanted effects, she notes, because “we do not know what other roles PCSK9 has in the body.” Fitzgerald says that in their experiments, the RNA didn’t appear to suppress the protein in other organs.

The new approach could be used with statins, Fitzgerald says. “What we’re very excited about here is, by the mechanism, you would expect that you get a synergetic effect with statins.”

Currently the experimental drug must be injected, but researchers are developing other ways for patients to take the drug, Fitzgerald says.

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Found in: Body & Brain and Genes & Cells