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Lab mice deaths cast doubt over RNAi

Setback for powerful therapy?

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A technology that has been lauded as a panacea for many currently incurable diseases has been dealt a blow by researchers. A paper appearing in Nature says mice given RNA interference therapy (RNAi) died of liver failure and other complications.

RNA is a close chemical relative of DNA. While DNA can be thought of as an unchanging leather-bound archive, RNA molecules are more like newspapers – dynamic, throwaway and with different agendas. RNA is the workhorse of biological information.

The principle behind RNAi is to use short double-stranded tracts of RNA as guided missiles, intercepting longer RNA messages which pass on information from DNA, before they can be used to make functioning proteins. It's thought to have developed early in evolution - bacteria use it too - as a means of combating viral infections.

Teams are working on harnessing its power to treat both deadly inherited conditions like Huntington's and infectious disease, such as HIV.

For this latest study, a team at Stanford medical school exposed mice to long-term high doses of RNAi. They tried out 49 different RNAi therapies designed to shut down six different genes in liver cells. 36 of the snippets caused liver injury, and 23 led to death within two months.

For biotech firms pumping millions into the field, the news may bring concerning echoes problems researchers have had fulfilling the potential of similarly promising gene therapy technology, which gave patients cancer in an early trial. Proponents say the study should act as a warning, but does not signal disaster for RNAi.

The Stanford team used an indirect approach to introduce the RNAi – they forced the mice's own cells to build them. The scientists speculate that this may have overloaded the cellular machinery, leading to the liver damage and deaths.

John Maraganore of biotech firm Alnylam Pharmaceuticals, which says it has already safely tested a respitory infection RNAi nasal spray told the NYT: "These data really represent the fundamental limitations of gene therapy, not of RNAi."

The authors of the study also note, despite the mouse deaths, other work they did proving the ability of RNAi to silence errant genes "fuels hope" of a whole new mode of attack against illness. ®

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