The Pharmaceutical Journal
Vol 273 No 7325 p709
13 November 2004

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New technique for switching off genes can reduce cholesterol levels in mice

New technique for switching off genes can reduce cholesterol levels in mice
Use of a technique called RNA interference (RNAi) to switch off a gene encoding apolipoprotein B (apoB) reduces cholesterol levels in mice, a recent study has shown. The research highlights RNAi as a potential new therapeutic strategy for treatment of patients with hypercholesterolaemia who are at increased risk of coronary heart disease.

RNAi involves the inactivation of genes by introduction of double-stranded RNA molecules into cells. Enzymes called dicers then cut these RNA strands into smaller RNA fragments called short-interfering RNA molecules (siRNAs). These induce degradation of messenger RNA encoding specific target proteins.

Hans-Peter Vornlocher and colleagues at Alnylam Pharmaceuticals in Germany and the US designed a specific siRNA molecule to inactivate the apoB gene, encoding a protein essential for processing cholesterol in mammals. Chemical modification of the siRNA molecule improved its stability and delivery to target cells compared with previous studies.

The researchers showed that 24 hours after intravenous injection in mice the apoB gene was switched off in liver and jejunum tissues, and production of apoB protein was reduced. Inactivation of the apoB gene by RNAi resulted in lower total cholesterol levels in treated mice and the researchers note that the levels of cholesterol reduction would be considered highly clinically significant in humans with hypercholesterolaemia (Nature 2004; 432:173).