Half the people taking cholesterol-lowering drugs can’t reduce LDL, the “bad” cholesterol associated with a high risk of heart disease, to an acceptable level. Now, scientists at Alnylam Pharmaceuticals, in Cambridge, MA, have found that a single dose of a new drug lowers cholesterol up to 60 percent in rodents and monkeys, with the effect lasting about three weeks. The drug might one day provide another option for patients who are resistant to existing cholesterol-lowering drugs due to genetic factors, or it might also be used in combination with existing cholesterol-lowering drugs to increase their effectiveness.
The drug employs an approach known as RNA interference, a principle that is being studied to develop drugs for many diseases, including cancer. With this technique, scientists create short RNA molecules that bind to messenger RNA in the cell, causing it to self-destruct. That interrupts the process of gene transcription, and thus the synthesis of the proteins coded by the gene. Alnylam’s new drug targets an enzyme called PCSK9, previously shown to affect LDL cholesterol levels and risk of heart disease.
PCSK9 is a hot drug target, says Kevin Fitzgerald, Alnylam’s director of research. But it’s difficult to find small molecules that block the enzyme directly because there’s no obvious place for those molecules to bind. The company’s findings demonstrate that blocking the production of PCSK9 with RNA interference works in nonhuman primates, and that it’s effective in a single dose, says study coauthor Jay Horton, a professor of internal medicine at UT Southwestern who focuses on digestive and liver diseases. The study appears online in the Proceedings of the National Academy of Sciences (PNAS).
Previous research has shown that PCSK9 plays an important role in determining LDL cholesterol levels in the blood. Mice that lack the PCSK9 gene have lower levels of cholesterol, and people with an ineffective form of the PCSK9 gene have lower levels of LDL and a dramatically lower risk of heart disease.
PCSK9 binds to LDL receptors on the surface of liver cells and causes those receptors to break down. Because LDL receptors sweep cholesterol from the blood, the goal is to keep their numbers high. “You want more LDL receptors, so blocking PCSK9 is a good thing,” says Horton.
But statins, which are commonly prescribed for lowering cholesterol, tend to trigger an increase in PCSK9 activity, says Henrik Ørum, vice president and chief scientific officer of Santaris Pharma, a company in Hørsholm, Denmark, that is also developing RNA interference drugs for lowering cholesterol. Ørum says that a drug that knocks down PCSK9 could be used in combination with a statin to increase the cholesterol-lowering effect.
For the PNAS study, the Alnylam researchers designed short, double-stranded RNA molecules to silence the gene for PCSK9 in rodents, monkeys, and humans. They packaged the molecules into lipid-based nanoparticles developed by biomedical engineer Robert Langer and his group at MIT. The nanoparticles protect the molecules in the bloodstream and escort them to liver cells.
Injecting the drug into mice and rats lowered total cholesterol by up to 60 percent, and in monkeys, a single dose cut LDL cholesterol by 50 to 60 percent. The reduction lasted about three weeks. Although PCSK9’s importance was clear from genetic studies in rodents and humans, “what was not known was, if you were to acutely knock down the level of PCSK9, how long would it take for cholesterol to go down,” Fitzgerald says. “The answer was, if you knock it down today, then your cholesterol is down tomorrow.”
It’s not yet clear how well an RNA-interference-based drug that requires injections could compete with existing medicines for lowering cholesterol. No such drugs have yet been approved by the Food and Drug Administration, although several are in clinical trials. While there have been some safety concerns with RNA-based therapeutics, scientists at Alnylam say that they saw no unacceptable side effects in animals given the cholesterol-lowering treatment, and people who naturally lack PCSK9 seem healthy.
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