Could RNA interfere with prion disease?
Genetic treatment shows promise against scrapie.
Prion diseases have become the newest target for treatment with RNA interference (RNAi). The gene-silencing technique has been used to prolong the lives of mice infected with scrapie, a disease similar to Creutzfeldt-Jakob disease (CJD).
But the news is bittersweet the high proportion of cells that must be treated with RNAi before seeing a beneficial effect means the approach is a long way from a cure for prion diseases in humans.
There is currently no treatment for prion diseases, which include CJD in humans and bovine spongiform encephalopathy (BSE) in cattle. They occur when normal prion proteins become knotted and resistant to being broken down, and cause rapid brain degeneration that is inevitably fatal.
One possible approach to fighting the diseases involves knocking out the presence of prions altogether, including both the normal and abnormal forms. Previous work has shown that mice with their prion gene knocked out remain healthy, and when inoculated with scrapie are protected against the disease1.
The team used RNAi to create transgenic mice in which the prion gene had been knocked out of a varying proportion of their cells. The technique worked, significantly extending mouse lifespan. But only if two-thirds or more of the cells had their prion-protein gene turned off.
Mice with the gene turned off in more than 65% of their cells survived almost 25% longer than controls, who succumbed within 174 days of scrapie infection. The team's results are reported online in the Journal of Clinical Investigation2.
Quelling this proportion of the protein in humans isn't currently possible. "I don't see today a device capable of this," says Pfeifer.
Adriano Aguzzi, a prion researcher at the University Hospital of Zurich in Switzerland, agrees that it would be incredibly difficult. "In order to get into a human brain the amount of RNA you get into a mouse's with a needle, you would have to go into the human brain with a garden hose. It's an engineering problem," he says.
But proving the principle is what's important, says Pfeifer. "Before we did this experiment it wasn't clear what amount you needed to get a therapeutic effect," he says. His team is now trialling ways of silencing this much of the gene in adult mice.
Livestock plagued by prion disease could see more immediate benefits. Creating transgenic cattle, pigs or sheep with the prion-protein gene knocked out work that has already begun3 could banish the disease from animals and perhaps prevent transmission to humans.
But it is not entirely clear what happens when the gene for normal prions is completely removed. Whereas mice with their prion-protein gene knocked out seem to be healthy, it is thought that the gene might also help to regulate the growth of stem cells in the brain and bone marrow, Pfeifer says.
In mice, the technique used to turn off the gene does its work in the early embryo, and perhaps the developing brain compensates for any ill effects. Switching off the gene in an adult brain, as would have to be done as a treatment for CJD, is a different matter.
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- Bueler H., et al. Cell, 73 . 1339 - 1347 (1993).
- Pfeifer A., et al. Journal of Clinical Investigation, doi:10.1172/JCI29236 (2006).
- Golding M., et al. PNAS, 103 . 5285 - 5290 (2006).