FOR the first time, an ancient form of cellular self-defence has been exploited to protect living animals against disease. If this “RNA interference” technique can be made to work in people too, it could one day be used to treat everything from cancer to HIV.
RNA interference (RNAi) exploits an ancient part of the immune system that protects plants and animals against invaders by shutting off their genes. It involves designing tiny RNA molecules that match part of the sequence of the messenger RNA copy of any target gene. These small interfering RNAs (siRNAs) switch on the host’s defence system, blocking production of the protein that the gene codes for (see 91av, 14 September 2002, p 32).
Geneticists studying plants and worms have exploited RNAi for some time. But the recent discovery of a similar system in mammalian cells has created much excitement, as it could be a powerful way to snuff out genes that trigger disease. Last year a flurry of studies showed that RNAi could be used to stop viruses replicating in human cells grown in the lab, and even shut down genes in mice. But that didn’t prove the technology was effective enough to treat disease.
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Work by Judy Lieberman’s team at Harvard Medical School in Boston now shows it can be. The researchers succeeded in protecting mice against liver disease using RNAi.
Their target was the gene coding for a protein called Fas, a receptor that sits on the surface of cells and triggers cell death when activated. Fas normally helps protect the body against cancer, but it can also be switched on by viruses, a malfunctioning immune system or chronic alcoholism, leading to a variety of liver diseases. “The liver has a lot of Fas, so it is very sensitive to this death receptor,” says Lieberman.
Lieberman’s team simply injected the anti-Fas siRNAs into the tails of mice. Nearly 90 per cent of liver cells took up the molecules, and the number of the Fas receptors on these cells fell dramatically, to almost undetectable levels.
Then, to mimic severe hepatitis, the researchers injected mice with antibodies that bind to Fas and trigger the cell suicide programme. While 40 normal mice all died within three days, 33 out of 40 mice that had been injected with siRNAs survived for 10 days. At that point the animals were killed so the team could examine their livers. The organs appeared completely normal (Nature Medicine, DOI: 10.1038/nm828).
“That’s pretty amazing considering this paper represents our first attempt,” says Lieberman. “We haven’t optimised it at all.”
Gregory Hannon, an RNAi researcher at Cold Spring Harbor Laboratory in New York State, agrees. “I wouldn’t have expected to see that good an effect in an organ, given the crude method of delivery,” he says. “It’s quite a nice demonstration of how this might work as a therapeutic.”
However, because people are so much larger than mice, simply injecting them with siRNAs probably will not work. But several groups are already working on ways to target siRNAs to specific organs.
