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Nucleic Acids Research Advance Access published online on November 16, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn904
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

Potent inhibition of microRNA in vivo without degradation

Scott Davis1, Stephanie Propp2, Susan M. Freier2, Laura E. Jones3, Martin J. Serra3, Garth Kinberger2, Balkrishen Bhat1, Eric E. Swayze2, C. Frank Bennett2 and Christine Esau1,*

1Regulus Therapeutics, 2Isis Pharmaceuticals, Carlsbad, CA 92008 and 3Allegheny College, Meadville, PA 16335, USA

*To whom correspondence should be addressed. Tel: +1 760 268 6842; Fax: +1 760 268 6802; Email: cesau{at}regulusrx.com

Received July 30, 2008. Revised October 24, 2008. Accepted October 28, 2008.

Chemically modified antisense oligonucleotides (ASOs) are widely used as a tool to functionalize microRNAs (miRNAs). Reduction of miRNA level after ASO inhibition is commonly reported to show efficacy. Whether this is the most relevant endpoint for measuring miRNA inhibition has not been adequately addressed in the field although it has important implications for evaluating miRNA targeting studies. Using a novel approach to quantitate miRNA levels in the presence of excess ASO, we have discovered that the outcome of miRNA inhibition can vary depending on the chemical modification of the ASO. Although some miRNA inhibitors cause a decrease in mature miRNA levels, we have identified a novel 2'-fluoro/2'-methoxyethyl modified ASO motif with dramatically improved in vivo potency which does not. These studies show there are multiple mechanisms of miRNA inhibition by ASOs and that evaluation of secondary endpoints is crucial for interpreting miRNA inhibition studies.


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