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Nucleic Acids Research Advance Access originally published online on December 19, 2006
Nucleic Acids Research 2007 35(2):687-700; doi:10.1093/nar/gkl1071
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Nucleic Acids Research, 2007, Vol. 35, No. 2 687-700
© 2006 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.

Chemistry

Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals

Eric E. Swayze*, Andrew M. Siwkowski, Edward V. Wancewicz, Michael T. Migawa, Tadeusz K. Wyrzykiewicz, Gene Hung, Brett P. Monia and and C. Frank Bennett

Isis Pharmaceuticals, Inc. 1896 Rutherford Road, Carlsbad, CA 92008,USA

*To whom correspondence should be addressed. Tel: +1 760 603 3825; Fax: +1 760 603 4653; Email: eswayze{at}isisph.com

Received August 18, 2006. Revised October 27, 2006. Accepted November 9, 2006.

A series of antisense oligonucleotides (ASOs) containing either 2'-O-methoxyethylribose (MOE) or locked nucleic acid (LNA) modifications were designed to investigate whether LNA antisense oligonucleotides (ASOs) have the potential to improve upon MOE based ASO therapeutics. Some, but not all, LNA containing oligonucleotides increased potency for reducing target mRNA in mouse liver up to 5-fold relative to the corresponding MOE containing ASOs. However, they also showed profound hepatotoxicity as measured by serum transaminases, organ weights and body weights. This toxicity was evident for multiple sequences targeting three different biological targets, as well as in mismatch control sequences having no known mRNA targets. Histopathological evaluation of tissues from LNA treated animals confirmed the hepatocellular involvement. Toxicity was observed as early as 4 days after a single administration. In contrast, the corresponding MOE ASOs showed no evidence for toxicity while maintaining the ability to reduce target mRNA. These studies suggest that while LNA ASOs have the potential to improve potency, they impose a significant risk of hepatotoxicity.


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