MicroRNA-like off-target transcript regulation by siRNAs is species specific
Abstract
siRNAs mediate sequence-specific gene silencing in cultured mammalian cells but also silence unintended transcripts. Many siRNA off-target transcripts match the guide-strand “seed region,” similar to the way microRNAs match their target sites. The extent to which this seed-matched, microRNA-like, off-target silencing affects the specificity of therapeutic siRNAs in vivo is currently unknown. Here, we compare microRNA-like off-target regulations in mouse liver in vivo with those seen in cell culture for a series of therapeutic candidate siRNAs targeting Apolipoprotein B (APOB). Each siRNA triggered regulation of consistent microRNA-like off-target transcripts in mouse livers and in cultured mouse liver tumor cells. In contrast, there was only random overlap between microRNA-like off-target transcripts from cultured human and mouse liver tumor cells. Therefore, siRNA therapeutics may trigger microRNA-like silencing of many unintended targets in vivo, and the potential toxicities caused by these off-target gene regulations cannot be accurately assessed in rodent models.
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Footnotes
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↵3 Present address: Regulus Therapeutics LLC, 1896 Rutherford Road, Carlsbad, CA 92008, USA.
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Reprint requests to: Peter S. Linsley, Regulus Therapeutics, 1896 Rutherford Road, Carlsbad, CA 92008, USA; e-mail: plinsley{at}regulusrx.com; fax: (760) 268-6868.
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Article and publication date are at http://www.rnajournal.org/cgi/doi/10.1261/10.1261/rna.1326809.
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- Received August 22, 2008.
- Accepted October 29, 2008.
- Copyright © 2009 RNA Society