Silencing RNA can be a powerful tool: but how does it work?
MEDI-MATION/SPL
Posted on 03/27/2008 12:40:57 AM PDT by neverdem
Two studies highlight promise and problems for gene silencing technique.
Silencing RNA can be a powerful tool: but how does it work?
MEDI-MATION/SPL
Researchers have managed to silence tiny chunks of RNA in monkeys using a gene-therapy technique. Their success could offer a new way to treat conditions from cancer to cardiovascular disease.
But another study of how RNA interference (RNAi) works — this time in mice — casts some doubt over how well researchers understand the process, and suggests caution in pursuing the technique in people.
In the monkey study, researchers looked at microRNAs (miRNAs) — small chunks of RNA that regulate genes and have a role in many diseases. Interfering with these small RNA molecules, rather than with the RNA that corresponds to single genes, offers a way to target whole pathways at once. That's a potentially powerful tool.
Sakari Kauppinen of Santaris Pharma, based in Hørsholm, Denmark, and his colleagues studied a miRNA that works in the liver to regulate metabolism of cholesterol and fat. By silencing it in African green monkeys, they could reduce the amount of cholesterol in the monkeys' blood, they report in Nature 1.
Researchers have been able to squash the effects of miRNAs in rodents, but Kauppinen says this is the first time the technique has been shown to work in primates.
The tiny RNA chunks and the pathways they govern may “provide novel therapeutic [avenues for diseases] that are not amenable to other applications,” Kauppinen says. The miRNA molecule he and his team silenced, called miR-122, also plays a part in hepatitis C. They say they hope to start clinical trials of miRNA interference against this infection later this year.
Confused action
But a second study, also in Nature, paints a less rosy picture of RNAi therapy. Jayakrishna Ambati at the University of Kentucky in Lexington and his colleagues studied the effects of RNAi on genes involved in a severe form of blindness called age-related macular degeneration (AMD). Trials of RNA-interfering drugs have already started in people with this disease — but the latest findings go against the accepted grain of how the technique works.
In severe forms of AMD, blood vessels grow across the retina and cause blindness. The idea is to suppress this growth by silencing a gene called VEGFA using a double-stranded molecule (a short interfering RNA, or siRNA) with a complimentary sequence. An siRNA called bevasiranib is being tested Phase III clinical trials for the treatment of AMD.
But when Ambati and his team looked at how siRNAs worked, they found that they could slow the growth of blood vessels no matter what sequence of siRNA molecule they used2. siRNAs “have a mechanism of action that is entirely different to what its purported to be,” says Ambati. Ambati suggests that rather than suppressing a specific gene, RNAi works in this case by triggering a general immune response in the eye, which reduces the growth of the vessels.
General response
This general response happens to be useful in AMD, but it may not be in other diseases. And it is problematic to think that researchers don't know how RNAi works. “Clinical trials should be approached with great caution,” says Ambati.
This isn’t the first time that caution has been urged over the unwanted effects of RNAi. But most off-target effects are caused by RNA molecules changing the expression of genes other than those they are aimed at, and not by initiating such a generalized response.
Most work supports the idea that RNAi works in a sequence-specific way, says Sam Reich, executive vice-president of OPKO Helath in Miami, which makes bevasiranib. He says he would “respectfully disagree” with Ambati's conclusions.
References Elmén, J. _et al. Nature doi:10.1038/nature06783 (2008). Kleinman, M. E. et al. Nature doi:10.1038/nature06765 (2008).
Sequence- and target-independent angiogenesis suppression by siRNA via TLR3
Maybe they hit some paydirt?
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Trouble is, many times when it comes to certain sequences of triggering gene expressions, often there are multiple paths.
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but of even more interest, generate favicons online:
Thanks for the links!
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