Monkey cholesterol levels cut by gene silencing

US, Canadian and German researchers have used a novel gene therapy approach to reduce blood cholesterol levels in monkeys by more than 60 per cent. The research, published in the journal Nature, uses a technique called RNAi (ribonucleic acid interference). The scientists - based at biotech firms Alnylam Pharmaceuticals and Protiva BioTherapeutics - say the study represents the first demonstration that RNA can be used to 'silence' a clinically relevant, disease-causing gene in primates.

RNAi is a naturally-occurring mechanism that scientists are trying to exploit as a way of selectively shutting down gene activity. The approach involves injecting cells with specific pieces of RNA, which then trigger the breakdown of a particular messenger RNA molecule - the intermediate stage between a gene and the protein it codes for. In this way, scientists can potentially selectively shut down production of any protein made by the cell, without affecting any others.

The Alnylam team had previously shown that they could use small RNA molecules to specifically destroy the messenger RNA for a protein called apoB, which controls blood cholesterol levels. They tested this approach in mice, and found that the levels of 'bad' LDL (low-density lipoprotein)-cholesterol dropped by 40 per cent in treated animals. In the latest study, the scientists encased the small pieces of RNA in a fatty envelope, before injecting them into monkeys. The fatty coating helped ensure the RNA treatment reached its target organ, the liver.

The researchers found that a single injection lowered blood cholesterol levels within 24 hours, and its effects lasted for up to 11 days. The level of apoB protein dropped by 75 per cent, causing a 60 per cent reduction in overall cholesterol and a drop in LDL-cholesterol of more than 80 per cent. The treatment did not cause any significant side effects in the 18 animals tested. Existing anti-cholesterol drugs, called statins, can cut harmful cholesterol levels by 40-60 per cent, but they have to be taken daily. John Maraganore, chief executive of Alnylam, said that the firm hopes to begin clinical trials within the next two years.

US gene therapy researcher John Rossi told the Scientist magazine that the findings 'bode well' for future RNAi trials. However, he cautioned that further work is necessary, particularly to investigate the effects of several doses of the treatment, as would be required for chronic liver problems.