title: Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals.
abstract: 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.
authors.affiliation: Isis Pharmaceuticals, Inc., 1896 Rutherford Road, Carlsbad, CA 92008, USA. eswayze@isisph.com
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Siwkowski
authors.forename: Edward V
authors.initials: EV
authors.lastname: Wancewicz
authors.forename: Michael T
authors.initials: MT
authors.lastname: Migawa
authors.forename: Tadeusz K
authors.initials: TK
authors.lastname: Wyrzykiewicz
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense / Q000737:chemistry* / Q000633:toxicity*; D051381:Rats
chemical_list: D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; C477371:locked nucleic acid