Free Republic
Browse · Search
Topics · Post Article

Skip to comments.

Triumphs and tribulations for RNA interference
Nature News ^ | 26 March 2008 | Kerri Smith

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?

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).

TOPICS: Culture/Society; News/Current Events; Technical
KEYWORDS: genetics; genomics; medicine; rnainterference
LNA-mediated microRNA silencing in non-human primates

Sequence- and target-independent angiogenesis suppression by siRNA via TLR3

Maybe they hit some paydirt?

1 posted on 03/27/2008 12:40:58 AM PDT by neverdem
[ Post Reply | Private Reply | View Replies]

To: El Gato; Ernest_at_the_Beach; Robert A. Cook, PE; lepton; LadyDoc; jb6; tiamat; PGalt; Dianna; ...
FDA probing suicide risks from asthma drug

How sperm and egg fuse into one - Fusion protein could be targeted to stop parasites from...

FReepmail me if you want on or off my health and science ping list.

2 posted on 03/27/2008 1:13:23 PM PDT by neverdem (I'm praying for a Divine Intervention.)
[ Post Reply | Private Reply | To 1 | View Replies]

To: neverdem

Trouble is, many times when it comes to certain sequences of triggering gene expressions, often there are multiple paths.

3 posted on 03/27/2008 1:30:05 PM PDT by djf
[ Post Reply | Private Reply | To 1 | View Replies]

To: Lancey Howard; EternalVigilance

Genetics ‘Central Dogma’ Is Dead
Creation-Evolution Headlines | September 12, 2007
Posted on 09/16/2007 6:45:54 PM EDT by GodGunsGuts

Prions found in urine | 13 October 2005 | Andreas von Bubnoff
Posted on 10/18/2005 3:23:50 AM EDT by neverdem

but of even more interest, generate favicons online:

4 posted on 03/28/2008 9:10:33 AM PDT by SunkenCiv ( updated Saturday, March 1, 2008)
[ Post Reply | Private Reply | To 1 | View Replies]

To: SunkenCiv

Thanks for the links!

5 posted on 03/28/2008 9:15:53 AM PDT by Lancey Howard
[ Post Reply | Private Reply | To 4 | View Replies]

Disclaimer: Opinions posted on Free Republic are those of the individual posters and do not necessarily represent the opinion of Free Republic or its management. All materials posted herein are protected by copyright law and the exemption for fair use of copyrighted works.

Free Republic
Browse · Search
Topics · Post Article

FreeRepublic, LLC, PO BOX 9771, FRESNO, CA 93794 is powered by software copyright 2000-2008 John Robinson