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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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October 12, 2011

siRNA - Toxicity in the Eye?

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Posted by Derek

siRNA technology has famously been the subject of a huge amount of work (and a huge amount of hype) and, more recently, a huge amount of uncertainty. Now a new report will add to that last pile. A group at the University of Kentucky says that they've identified a toxic effect in the retina for a wide range of siRNAs, one that seems to be triggered independent of sequence:

"We now show a new undesirable effect of siRNAs that are 21 nucleotides or longer in length: these siRNAs, regardless of their sequence or target, can cause retinal toxicity. By activating a new immune pathway consisting of the molecules TLR3 and IRF3, these siRNAs damage a critical layer of the retina called the retinal pigmented epithelium (RPE). Damage to the RPE cells by siRNAs can also lead to secondary damage to the rods and cones, which are light-sensing cells in the retina. . ."

That's especially worrisome news, since several siRNA efforts have targeted eye diseases in particular. The eye is a privileged compartment, metabolically, and exotica like small RNA molecules have a better chance of surviving there. But if you're trying to help out with macular degeneration or diabetic retinopathy, affecting the retinal epithelium isn't what you need, is it?

As a side note, this effect seems to be mediated, in part, by TLR3. Its family, the toll-like receptors, were part of this year's Nobel in Physiology/Medicine.

Comments (14) + TrackBacks (0) | Category: Toxicology


COMMENTS

1. Benji on October 12, 2011 8:44 AM writes...

Retina tox. Awefully reminiscent of a certain BTI inhibitor!

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2. anchor on October 12, 2011 8:47 AM writes...

Goes back to show that siRNA technology will not go away silently. My question regarding to this retinal toxicity is for a siRNA molecule or across the board. response from anyone deeply appreciated.

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3. Wile E Coyote, Genius on October 12, 2011 9:29 AM writes...

Not a terribly surprising result. With the eye being an immune privilege site with the absence of immune cells migrating through (adaptive immunity), then innate immunity systems would come to the fore. With many viruses being single strand nucleotide based (or producing single stand oligos during replication), then this makes sense.

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4. pete on October 13, 2011 12:10 AM writes...

Can't say I've kept up closely with the field these days but I'm guessing these kind of issues have been known for some time by companies such as Alnylam. So, although they recently got patent on VEGF iRNA, there's no mention of antivascular indications (e.g., iRNA ==> AMD) in their current pipeline.

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5. Anon on October 13, 2011 1:19 AM writes...

RE Pete:

There are still companies that have a focus on the use of siRNA in the eye. See for example Antisense Therapeutics (UK based company) which lists PF-4523655 as being in Phase II for treating Diabetic Macular Edema and Age-related Macular Degeneration.
Perhaps they have run into similar problems?

Silly question but could one not just take an immunosuppressant in combination with the siRNA to reduce the immune response?

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6. pete on October 13, 2011 1:59 AM writes...

@5 Anon
Not a silly question, but in my non-MD capacity I believe it wouldn't fly in AMD since such a combo would likely be considered "clinically difficult" -- esp. in light of other, newer treatment options.

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7. Anonymous on October 13, 2011 6:27 AM writes...

The trick is to get a highly potent siRNA and use a very low dose to avoid innate immune reponse

Permalink to Comment

8. Wile E Coyote, Genius on October 13, 2011 7:21 AM writes...

@5 Anon,

The strategy of an immunosuppressant in combination with the siRNA would not work, as immunosuppressants do not suppress the innate immune system, such as TLRs, but are most effective against the adaptive immune system (lymphocytes).

Permalink to Comment

9. pete on October 13, 2011 11:33 AM writes...

@8 Wile
Good point -- wasn't sure if some retinal damage might depend on leukocyte infiltration, but apparently it doesn't (?)

Permalink to Comment

10. JC on October 13, 2011 12:29 PM writes...

It's always fun until someone gets hurt in eye.

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11. Charles U. Farley on October 13, 2011 12:58 PM writes...

This is definitely not news. Naked (unformulated) and unmodified (standard RNA nucleotides) siRNAs are neither cutting-edge nor serious leads in any serious pipelines for systemic indications...

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12. Eric Suh on October 13, 2011 1:13 PM writes...

Looks like a validation of the last sentence from this 2008 Nature paper: "Multiple human endothelial cell types expressed surface TLR3, indicating that generic siRNAs might treat angiogenic disorders that affect 8% of the world's population, and that siRNAs might induce unanticipated vascular or immune effects."

http://www.nature.com/nature/journal/v452/n7187/abs/nature06765.html

Permalink to Comment

13. Wile E. Coyote, Genius on October 13, 2011 1:25 PM writes...

Pete,

I don't have access to the paper, but it indicates that the result of the TLR activation is apoptosis and loss of RPE (without any inflammatory input). Loss of RPE is consequential to the retina and would be significant. It is the role of the RPE to phagocytose and process effete rod and cone platelets that are shed, among other functions.

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14. Givn'r on October 13, 2011 1:27 PM writes...

This is well known. Naked siRNAs will activated TLR receptors and trigger an innate immune response. To get around this, many groups use slightly chemically modified siRNAs. Usually a few 2'-OMe modifications on the 3'-end of the molecule will do the trick. End of story. Either the authors were oblivious to this or they are trying to sand bag an already bruised field. A shame.

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