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

被引：341

作者：

Swayze, Eric E. ^{[1
]}

Siwkowski, Andrew M. ^{[1
]}

Wancewicz, Edward V. ^{[1
]}

Migawa, Michael T. ^{[1
]}

Wyrzykiewicz, Tadeusz K. ^{[1
]}

Hung, Gene ^{[1
]}

Monia, Brett P. ^{[1
]}

Bennett, C. Frank ^{[1
]}

机构：

[1] ISIS Pharmaceut, Carlsbad, CA 92008 USA

来源：

NUCLEIC ACIDS RESEARCH | 2007年 / 35卷 / 02期

关键词：

NECROSIS-FACTOR-ALPHA; HUMAN RNASE H1; DIABETIC MICE; PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDES; APOLIPOPROTEIN-B; GENE-EXPRESSION; MESSENGER-RNA; KINASE PKR; PROTEIN; APOPTOSIS;

D O I：

10.1093/nar/gkl1071

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：687 / 700

页数：14

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[1] Second generation antisense oligonucleotides-inhibition of PKC-alpha and c-RAF kinase expression by chimeric oligonucleotides incorporating 6'-substituted carbocyclic nucleosides and 2'-O-ethylene glycol substituted ribonucleosides [J].