Way opens to switch off damaging genes

By STEVE CONNOR

Scientists have made a breakthrough in the clinical use of a revolutionary technique for treating potentially fatal diseases.

The researchers have shown for the first time that the technique of RNA interference can cut cholesterol levels in laboratory mice.

The technique switches off harmful genes, using a method that could be applied to human patients at risk of heart attacks.

Scientists say the study is exciting because it suggests that the same method of using RNA interference could be used to treat a wide range of other disorders, from HIV and Aids to genetic diseases and cancer.

RNA interference (RNAi) is considered one of the most important discoveries in medical science for decades because of its power to switch off the harmful genes involved in causing disease while leaving other essential genes untouched.

However, although test-tube experiments have demonstrated the power of RNAi to block viruses or to switch off cancer-causing genes, scientists have yet to demonstrate a reliable and safe way of using it on real patients.

Now researchers led by Hans-Peter Vornlocher, head of research at the pharmaceuticals company Alnylam Europe, have devised a relatively simple way of delivering RNAi to all the cells of the body via an injection into the bloodstream.

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 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 in order to allow the RNA to slip through the cell membranes of the body.

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

Results published 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 that the findings were a very exciting development in the design of new treatments for many of the incurable diseases affecting humanity.

"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.

"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, California, who is working on ways of using RNAi to treat patients with Aids, said that the Alnylam technique of attaching RNA molecules to cholesterol was potentially very important.

"It is hoped that 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 wrote in a Nature editorial.

"The beauty of these results is the relative simplicity of the delivery method."

Further research was needed to monitor potential side-effects and to assess how long the effect persisted without the need for further injections, Dr Rossi said.

Andrew Hamilton, lecturer in gene regulation and mechanisms of disease at the University of Glasgow, echoed the need for more work before the technique could be used on humans.


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