ONE of the most reviled substances in medicine could lead to new treatments for a wide range of diseases. By using cholesterol to stabilise tiny pieces of interfering RNA, researchers at biotech company Alnylam have been able to shut down a specific gene in animals using a simple injection.
鈥淭his is a pretty simple solution to the daunting problem of delivery that people thought would hold up the technology,鈥� says John Rossi, an RNA interference researcher at the City of Hope hospital in Duarte, California, who has no connection with Alnylam. 鈥淚f this works for other disease genes and viral targets, it will revolutionise the use of RNAi.鈥�
鈥淚f this works for other disease genes and viral targets, it will revolutionise the use of RNA interference鈥�
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RNAi works like this. When a gene is switched on, it produces messenger RNAs that are used to make the protein the gene encodes. But if small interfering RNAs (siRNAs) with a sequence matching part of a particular gene get into a cell, an ancient defence system is activated that destroys all the messenger RNAs, blocking production of the protein.
The medical potential is huge. The ability to shut down genes at will offers new ways of treating everything from cancer and viral infections to certain inherited diseases. And designing siRNAs that silence a specific gene is far easier and faster than any of the methods used to discover conventional drugs.
The tricky part is getting siRNAs into cells. Swallow them, and they are destroyed. Inject them into the blood, and they are quickly chewed up by enzymes. And even if they did not get pulverised, few siRNAs would end up inside cells. Researchers have had some success delivering siRNAs using tricks such as injecting them under high pressure or delivering them directly to one organ, such as the eye: an siRNA treatment for a retinal disease will be the first RNAi therapy to get to human trials.
But these methods are limited. The aim of researchers is to deliver siRNAs by a pill or injection, like conventional drugs. 鈥淲e wanted to give siRNAs drug-like properties 鈥� stability, bioavailablity 鈥� and joining them to cholesterol helped us do that,鈥� says Hans-Peter Vornlocher of Alnylam Europe in Kulmbach, Germany.
Together with some chemical changes to toughen the backbone of the siRNAs, the added cholesterol allows the siRNAs to bind to proteins in the blood, increasing their stability 15-fold. And the fatty molecule also helps siRNAs sneak inside cells, although the exact mechanism for this is not understood.
To test these souped-up siRNAs, the researchers chose, somewhat confusingly, to silence a gene called apoB that controls the level of cholesterol in blood. When mice were injected with cholesterol-linked siRNAs designed to target apoB, the blood levels of the apoB protein dropped by nearly 70 per cent 鈥� and cholesterol levels also plunged. Non-cholesterol-linked siRNAs or siRNAs that were not perfect matches to the apoB sequence had no effect (Nature, vol 432, p 173).
In the near term, siRNAs do not pose any serious competition for existing cholesterol-fighting drugs such as statins. It is not yet clear if the siRNAs鈥� effects last longer than 24 hours, for instance, and the large doses needed would be very expensive.
But it appears the technique could be adapted to silence genes involved in wide range of diseases. Although the apoB gene is only active in the liver and intestine, the modified siRNAs were also able to penetrate many other tissues, including heart, kidney, fat and lung.
The Alnylam team is not alone in trying to crack the delivery problem. Rossi says a number of other siRNA delivery strategies will be published in the next few months. And Vornlocher says his team isn鈥檛 finished with its chemical tinkering. He hopes to make siRNAs even more efficient, longer-lasting and perhaps even able to home in on particular tissues. How? 鈥淭hat鈥檚 all I鈥檓 prepared to say right now,鈥� he says.