New gene therapy targets cholesterol - health - 17 May 2007 - New Scientist

New gene therapy targets cholesterol - health - 17 May 2007 - New Scientist

First there was gene therapy, then came RNA interference. Now the latest technology promising to regulate gene expression has been used therapeutically for the first time - if only in mice - to cut cholesterol levels. The technique, termed microRNA (miRNA) inhibition, has also been used to stop hepatitis C infecting cells.

It is related to earlier forms of RNA interference (RNAi), such as siRNA - in which a double-stranded "short interfering RNA" is used to intercept and destroy messenger RNA (mRNA) before it can be translated into protein. But unlike siRNA, which works to silence genes, miRNA inhibition increases the amount of protein that gets produced by intercepting the molecules - miRNAs - that normally act as a brake on mRNA translation (see Diagram).

MicroRNAs are thought to control up to 30 per cent of all gene activity, with one type responsible for directing the expression of whole networks of genes, rather than just single genes. Changes in the expression of miRNAs have been implicated in cancer and other diseases, including viral infections (New Scientist, 11 June 2005, p 18).

RNAi-based therapies have so far failed to take off because of the difficulty of getting the therapeutic molecules into target cells, but according to work conducted at Santaris Pharma in Hørsholm, Denmark, miRNA-inhibiting drugs appear to be readily absorbed by cells without the need for a separate delivery vehicle. The company has been targeting an miRNA called miR-122, which is thought to regulate up to 450 genes, around 100 of which are involved in cholesterol and lipid metabolism. It is only expressed in liver cells.

Santaris created short, single-stranded RNA molecules designed to bind specifically to miR-122 and injected them into mice. This miRNA inhibitor, or antimiR, was readily taken up by liver cells and lowered cholesterol by up to 35 per cent. Inhibiting miR-122 also seems to protect the liver against hepatitis C infection, tests on cell cultures suggest.

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