Targeting the RNA of a single gene can successfully lower cholesterol levels in mice, according to a new study that may point the way to wider applications of the promising technique known as RNA interference.
Only a few years ago, researchers discovered that all organisms besides bacteria control gene expression, in part, using a mechanism called RNA interference. That kicked off a stampede to find a way to exploit it for medical purposes. The approach is simple in theory: Create a so-called short interfering RNA (siRNA) molecule that prevents the RNA of a disease-causing gene from being translated into protein. This strategy has worked in vitro, but when injected into a patient, siRNAs are not easily taken up by cells.
Taking a fresh approach, a team led by molecular biologist Hans-Peter Vornlocher of Alnylam Pharmaceuticals in Kulmbach, Germany, tried to tackle the problem of high cholesterol using siRNA. Dangerous levels of artery-clogging cholesterol in the blood are caused in part by overexpression of a gene called apoB. The team designed an siRNA to bind to apoB RNA and attached a single cholesterol molecule to one end. They hoped that the fat-soluble cholesterol would guide the siRNA through cell membranes to the cytoplasm where apoB RNA is translated into the cholesterol-boosting protein. They then injected it into the bloodstream of mice with high cholesterol levels.
The results were better than the researchers had expected: The modified anti-apoB siRNAs caused cholesterol levels in mice to drop as low as those in mutant mice with the apoB gene deleted. The treatment cut apoB protein expression by more than 50% in many major organs, including the liver, which makes cholesterol, the team reports 11 November in Nature. They point out that in principle their cholesterol-siRNA delivery system could be used to guide siRNA to silence any disease-causing genes.
John Rossi, a molecular biologist at the Beckman Research Institute in Duarte, California, calls the study "an important proof of principle" that injected siRNAs can be used to treat disease, but he cautions that there's still a long way to go. Until the treatment's potency is vastly improved, "impractical" quantities of siRNAs would have to be regularly injected for an entire lifetime. But, he adds, for otherwise untreatable diseases, even this might be a step forward.