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October 12, 2011
siRNA - Toxicity in the Eye?
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.
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