[extropy-chat] Technique for 'turning off' danger genes cuts cholesterol

[Damien Broderick]

http://news.independent.co.uk/world/science_technology/story.jsp?story=581597

By Steve Connor, Science Editor

11 November 2004

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."


10 November 2004 20:28