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Synthetic Dicer-Substrate siRNAs as Triggers of RNA Interference

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RNA Interference from Biology to Therapeutics

Part of the book series: Advances in Delivery Science and Technology ((ADST))

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Abstract

The first synthetic oligonucleotides used to suppress gene expression in mammalian cells via RNA interference were 21-nucleotide (nt) RNA duplexes having symmetric 2-nt 3′-overhangs and were designed to mimic the natural products of Dicer processing of long RNA substrates. Synthetic RNA duplexes which are longer than 23-nt length are substrates for processing by Dicer and can show increased potency as artificial triggers of RNA interference, particularly at a low concentration. Longer duplexes, however, can have variable cleavage patterns following Dicer processing which can adversely affect potency. Optimized synthetic Dicer substrates are asymmetric duplexes having a 25-nt passenger strand and a 27-nt guide strand with a single 2-nt 3′-overhang on the guide strand and modified bases at the 3′-end of the passenger strand. This modified design results in predictable patterns of Dicer processing and shows improved activity. The development of this design strategy and use of Dicer-substrate RNAs to trigger gene suppression in a variety of systems will be reviewed in this chapter.

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Acknowledgments

The authors thank Kim Lennox for critical reading of the manuscript and Dr. Joe Dobosy for assistance with the figures. We further thank Dr. John Rossi, Dr. Dongho Kim, and all members of the research laboratories at Integrated DNA Technologies for their contributions towards the development of the Dicer-substrate siRNA technology.

Conflict of Interest Statement

MAB and SDR are employed by Integrated DNA Technologies (IDT), which sells compounds similar to those described herein. IDT is, however, not a publicly traded company, and the authors do not hold any stock or equity in IDT. MAB is a scientific cofounder of Dicerna Pharmaceuticals and is a member of their Scientific Advisory Board.

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  1. Integrated DNA Technologies, Inc., 1710 Commercial Park, Coralville, IA, USA

    Scott D. Rose PhD & Mark A. Behlke MD, PhD

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  1. Scott D. Rose PhD
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  2. Mark A. Behlke MD, PhD
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Correspondence to Mark A. Behlke MD, PhD .

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  1. Interdisciplinary Nanoscience Center, Aarhus University, Ny Munkegade 118, Aarhus, 8000 AA, Denmark

    Kenneth A. Howard

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Rose, S.D., Behlke, M.A. (2013). Synthetic Dicer-Substrate siRNAs as Triggers of RNA Interference. In: Howard, K. (eds) RNA Interference from Biology to Therapeutics. Advances in Delivery Science and Technology. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-4744-3_2

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