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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

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March 28, 2008

RNA Interference: Even Trickier Than You Thought

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Posted by Derek

It’s been a while since I talked about RNA interference here. It’s still one of those tremendously promising therapeutic ideas, and it’s still having a tremendously hard time proving itself. Small RNA molecules can do all sorts of interesting and surprising things inside cells, but the trick is getting them there. Living systems are not inclined to let a lot of little nucleic acid sequences run around unmolested through the bloodstream.

The RNA folks can at least build on the experience (long, difficult, expensive) of the antisense DNA people, who have been trying to dose their compounds for years now and have tried out all sorts of ingenious schemes. But even if all these micro-RNAs could be dosed, would we still know what they’re going to do?

A report in the latest Nature suggests that the answer is “not at all”. This large multi-university group was looking at macular degeneration, a natural target for this sort of technology. It’s a serious disease, and it occurs in a privileged compartment of the body, the inside of the eye. You can inject your new therapy directly in there, for example (I know, it gives me the shivers, too, but it sure beats going blind). That bypasses the gut, the liver, and the bloodstream, and that humoral fluid of the eye is comparatively free of hostile enzymes. (It’s no coincidence that the antisense and aptamer people have gone after this and other eye diseases as well).

Angiogenesis is a common molecular target for macular regeneration, since uncontrolled formation of new capillaries is a proximate cause of blindness in such conditions. (That target has the added benefit of giving your therapy a possible entry into the oncology world, should you figure out how to get it to work well here). VEGF is the prototype angiogenesis target, so you’d figure that RNA interference targeting VEGF production or signaling would work as well as anything could, as a first guess.

And so it does, as this team found out. But here comes the surprise: when the researchers checked their control group, using a similar RNA that should have been ineffective, they found that it was working just fine, too – just as well as the VEGF-targeted ones, actually. Baffled, they went on to try a host of other RNAs. Reading the paper, you can just see the disbelief mounting as they tried various sequences against other angiogenic targets (success!), nonangiogenic proteins (success!?), proangiogenic ones that should make the disease worse (success??), genes for proteins that aren’t even expressed in the eye (success!), sequences against RNAs from plants and microbes that don’t even exist in humans at all (oh God, success again), totally random RNAs (success, damnit), and RNAs that shouldn’t be able to silence anything because they’ve got completely the wrong sort of sequence (oh the hell with it, success). Some of these even worked when injected i.p., into the gut cavity, instead of into the eye at all, suggesting that this was a general mechanism that had nothing to do with the retina.

As it turns out, these things are acting through hitting a cell surface receptor, TLR3. And all you need, apparently, is a stretch of RNA that’s at least 21 units long. Doesn’t seem to matter much what the sequence is – thus all that darn success with whatever they tried. Downstream of TLR3 come induction of gamma-interferon and IL-12, and those are what are doing the job of shutting down angiogenesis. (Off-target effects involving these have been noted before with siRNA, but now I think we’re finally figuring out why).

What does this all mean? Good news and bad news. The companies that are already dosing RNAi therapies for macular degeneration have just discovered that there's an awful lot that they don't know about what they're doing, for one thing. On the flip side, there are a lot of human cell types with TLR3 receptors on them, and a lot of angiogenic disorders that could potentially be treated, at least partially, by targeting them in this manner. That’s some good news. The bad news is that most of these receptors are present in more demanding environments than the inside of the eye, so the whole problem of turning siRNAs into drugs still looms large.

And the other bad news is that if you do figure out a way to dose these things, you may well set off TLR3 effects whether you want them or not. Immune system effects on the vasculature are not the answer to everything, but that may be one of the answers you always get. And this sort of thing makes you wonder what other surprising things systemic RNA therapies might set off. We will, in due course, no doubt find out. More here from John Timmer at Nobel Intent, who correctly tags this as a perfect example of why you want to run a lot of good control experiments. . .

Comments (4) + TrackBacks (0) | Category: Biological News | Drug Development


COMMENTS

1. kay on March 28, 2008 3:50 PM writes...

"Off-target effects involving these have been noted before with siRNA, but now I think we’re finally figuring out why"
It has been known for quite a while that short dsRNA can induce a gamma-interferon response, and TLR3 as a known dsRNA receptor signaling via TRIF is the obvious culprit. RNAi will give you all kinds of effects (I have listed a few of them in my own post at http://suicyte.wordpress.com/2008/03/28/strange-paper-ii/). What is special about this particular paper is that the desired therapeutic effect is caused by this non-specific action. There are probably many more examples where the non-specific siRNA response will cause something undesirable.

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2. Alan Hochberg on March 28, 2008 4:24 PM writes...

Great article. In 1975 when monoclonal antibodies were first announced, we thought they would be turned into human drugs within about 5 years. Now it's the RNAi folks' turn to find out just how tricky the human body is.

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3. SciChick on March 28, 2008 6:32 PM writes...

Oh how did I miss this new hot Nature article?? Thanks for pointing it out...very interesting indeed. RNAi is a topic near-and-dear to my heart - I am a postdoc working on developing delivery systems for siRNA. You know it's so true that without the proper controls, you can make believe ANYTHING. I mean, we are just testing these things in cell culture (what a nice little well-controlled model), and if you sample the literature in this particular area (delivery), you see all sorts of crap (seriously, CRAP) done by all sorts of non-biologists (not hardcore molecular or cell biologists, anyway) ranging from chemists, Chem Es, Biomed Es...and the lack of control experiments in these publications is disgusting. I myself am not the one to speak about this, for I am a chemist by training and I have no idea whatsoever about the complicated mammalian cells; but when you see people who don't include the proper controls, or drawing way too many conclusions from one little experiment, you start to wonder how valid their whole paper is. It is a double-edged sword - for a field this hot and new, there is plenty of hope, but also plenty of hype.

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4. drug_hunter on March 29, 2008 7:06 AM writes...

Good thing Fire & Mello already won their Nobel!

But there is in the same issue of Nature a more upbeat article about microRNA. So there is hope.

www.nature.com/news/2008/080326/full/news.2008.693.html

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