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RNAi to the Liver's Rescue
10 February 2003 (All day)
Shooting millions of tiny RNA molecules into a mouse's bloodstream can protect its liver from the ravages of hepatitis. This is apparently the first time that the technique, called RNA interference (RNAi), has been used to fight disease in an animal. But biologists caution that the therapy has a long way to go before it can be safely applied to humans.
RNAi uses miniature RNA molecules to silence specific genes (ScienceNOW, 19 December 2002). Normally, large RNA molecules convert genetic information into proteins; but in the late 1990s, researchers found that truncated RNAs could be coaxed to turn genes off. Hepatitis has become a focus of RNAi studies, because the liver readily absorbs the molecules.
Harvard University immunologists Judy Lieberman and Premlata Shankar and their colleagues wanted to see if RNAi could prevent liver damage. They gave mice three massive high-pressure injections--equivalent to about half the animals' blood volume--of a solution that forced the molecules into the liver. The molecules were designed to shut down a gene called Fas, which, when overactivated, induces liver cells to self-destruct; Fas is also involved in human liver diseases.
The next day, the animals got an antibody that sends Fas into hyperdrive, causing liver failure. Control mice died within a few days, but 82% of the treated mice survived. About 80% to 90% of liver cells had incorporated the RNA molecules. Furthermore, the RNA molecules hung around for 3 weeks, roughly three times longer than previous studies, the authors report today online in Nature Medicine.
Meanwhile, other mice faced a separate challenge: Over 6 weeks, they received weekly injections of cells called ConA, which goad the immune system to attack the liver, producing the kind of scarring seen in viral hepatitis. Some animals also got an RNA infusion during this time, and that group developed no liver damage. Despite the traumatic delivery method, the mice didn't appear to suffer side effects.
"It's amazing how well it worked," marvels Charles Rice of Rockefeller University in New York City. Still, he adds, the delivery method is clearly problematic: In humans, "hydrodynamic shock ... is not the way to go." Researchers have yet to determine whether a gentler approach might prove successful.