Technique for 'turning off' danger genes is used to cut cholesterol

Scientists have found a way of treating potentially fatal diseases by switching off harmful genes. In what is described as one of the most important breakthroughs in decades, researchers have shown that RNA interference can cut cholesterol levels in laboratory mice with a method that could be applied to humans at risk of heart attacks.

Scientists have found a way of treating potentially fatal diseases by switching off harmful genes. In what is described as one of the most important breakthroughs in decades, researchers have shown that RNA interference can cut cholesterol levels in laboratory mice with a method that could be applied to humans at risk of heart attacks.

They say RNA interference (RNAi) could be used to treat a wide range of disorders, from HIV and Aids to genetic diseases and cancer. RNAi can switch off harmful genes that cause disease but leave other essential genes untouched.

Science had not previously demonstrated a safe, reliable way of using it on patients, but now researchers led by Hans-Peter Vornlocher, head of research at the pharmaceuticals company Alnylam Europe, have devised a simple method of delivering RNAi to all the cells of the body via an intravenous injection. In experiments on mice they injected short lengths of RNA - a molecule similar to DNA - that had been designed to switch off or "silence" the gene responsible for producing apoliprotein B, a protein involved in the synthesis of the damaging form of cholesterol.

By coincidence, the researchers used another form of the cholesterol molecule, which they had attached to the RNA molecule to allow the RNA to slip through the cell membranes of the body.

"The idea is that the lipophilic [fat-attracting] population of cholesterol molecules will act as a Trojan horse to get the RNA into the cells," Dr Vornlocher said.

Results in the journal Nature showed that the technique successfully silenced the gene for apoliprotein B and consequently cut cholesterol levels in the bloodstream of the injected mice by up to a half. Dr Vornlocher said: "We have meaningfully advanced the field of RNAi. We think we can transfer the work into a human setting."

Julian Downward, an expert in RNAi at Cancer Research UK, said the findings were a very exciting development in the design of new treatments for many incurable diseases. "For the first time it harnesses the great potency and specificity that RNA interference has shown in the lab to a format that can be used in patients in the clinic," Dr Downward said. "This brings the prospect of uniquely targeted therapies a big step closer, even for diseases that have previously proven hard to develop conventional drugs against."

John Rossi of the Beckman Research Institute of the City of Hope in Duarte in California, who is working on ways of using RNAi to treat patients with Aids, said the Alnylam technique of attaching RNA molecules to cholesterol is potentially very important."It is hoped this approach might be used to shut down disease-related genes in humans; with [this study in mice] that dreams moves a little closer to reality," Dr Rossi says in a Nature editorial. "The beauty of these results in the relative simplicity of the delivery method."

Further research is, however, needed to monitor potential side-effects and to assess how long the effect persists without the need for further injections. Andrew Hamilton, lecturer in gene regulation and mechanisms of disease at the University of Glasgow, said: "It's one more step toward the clinic for RNAi."

"Although there may be many diseases we could treat with RNAi-based medicine, we need more work on targeting, efficiency, persistence and possible side-effects."

John Maraganore, chief executive of Alnylam, said: "We are committed to working on direct and systemic applications of RNAi in cardiovascular disease, diabetes, obesity, hepatitis, cancer and many infectious diseases."