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

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, L...

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Bibliographic Details
Published in:Nucleic acids research 2007-01, Vol.35 (2), p.687-700
Main Authors: Swayze, Eric E, Siwkowski, Andrew M, Wancewicz, Edward V, Migawa, Michael T, Wyrzykiewicz, Tadeusz K, Hung, Gene, Monia, Brett P, Bennett, and C. Frank
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Cells, Cultured
Chemical and Drug Induced Liver Injury
Chemistry
Liver - drug effects
Liver - pathology
Liver Diseases - pathology
Male
Mice
Mice, Inbred BALB C
Oligonucleotides
Oligonucleotides, Antisense - chemistry
Oligonucleotides, Antisense - toxicity
Rats
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkl1071