Single-stranded microRNA mimics

  1. Lee P. Lim8,9
  1. Sirna Therapeutics, a wholly owned subsidiary of Merck & Co., San Francisco, California 94158, USA

    1. ↵1 These authors contributed equally to this work.

    • ↵2 Present address: Aegis Advisors, Hong Kong, China

    • ↵3 Present address: University of Michigan Ross School of Business, Ann Arbor, MI 48109, USA

    • ↵4 Present address: Novartis, Emeryville, CA 94608, USA

    • ↵5 Present address: Sapphire Energy, San Diego, CA 92121, USA

    • ↵6 Present address: Genentech, South San Francisco, CA 94080, USA

    • ↵7 Present address: Merck Research Laboratory, Palo Alto, CA 94304, USA

    • ↵8 Present address: Department of Surgery, UCSF, San Francisco, CA 94143, USA

    Abstract

    miRNAs are ∼22-nt RNAs that bind to the Argonaute family of proteins and have important regulatory roles in plants and animals. Here, we show that miRNAs exhibit targeting activity in cells when delivered as single strands that are 5′-phosphorylated and that contain 2′-fluoro ribose modifications. Length preferences, chemical modification sensitivity, and genome-wide seed-based targeting all suggest that this activity is Ago-based. Activity could be enhanced by annealing of segmented passenger strands containing non-nucleic acid spacers. Furthermore, screening of randomly generated sequences identified pyrimidine rich 3′ cassette sequences that increased single strand activity. These results provide an initial step in the development of single-stranded miRNA mimics for therapeutic use.

    Keywords

    Footnotes

    • Received November 9, 2011.
    • Accepted June 22, 2012.
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    1. Published in Advance August 21, 2012, doi: 10.1261/rna.031278.111 RNA 18: 1796-1804 Copyright © 2012 RNA Society

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