Toward a plausible RNAi therapy />
CONTEXT: RNA interference (RNAi) – once thought to be an experimental artifact, then considered an unimportant anomaly – is now recognized as an important technique for regulating gene expression in animals, plants, and fungi. In essence, RNAi occurs when small RNA molecules (short interfering RNA or siRNA) ambush messenger RNA, the molecule through which the instructions in a gene are translated into the protein that will act them out. At least three companies hope to transform the technology into new therapies. It’s tough to do, because siRNA is rapidly destroyed in blood and has trouble getting into cells. Now, a team that is headed by Jürgen Soutschek and Hans-Peter Vornlocher at the biotech company Alnylam has shown that a new version of siRNA can travel through the bloodstream into cells and lower cholesterol levels.
METHODS AND RESULTS: Soutschek and colleagues made siRNA that would silence the gene for a cholesterol-boosting protein, apolipoprotein B. Using established techniques, they modified the chemical backbone of siRNA to make it more stable. In a novel approach, they linked siRNA to another molecule (ironically, cholesterol) that enters cells easily and injected the linked molecules into mice. The treatment lowered “bad” cholesterol levels by more than 40 percent, and follow-up tests showed that siRNA had entered cells and stopped production of apolipoprotein B.
WHY IT MATTERS: Drugs available today work in just a handful of ways. Most bind to a protein and affect its function. Others replace a protein. RNAi drugs would do something completely different: they would stop a protein from being made at all, and so treat diseases in ways that other techniques cannot. By showing that RNAi drugs can be delivered through blood, this research counters the strongest criticism of the technique. But more obstacles remain: in humans, siRNA must travel farther in the bloodstream than in mice, the amounts of drug required are still prohibitively high, and long-term treatments with cholesterol-linked siRNA may have side effects worse than the disease. Nonetheless, these results, and more like them, will begin to sway the skeptics.
SOURCE: Soutschek, J., et al. 2004. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432:173-178.