Comparison of hepatic transcription profiles of locked ribonucleic acid antisense oligonucleotides: evidence of distinct pathways contributing to non-target mediated toxicity in mice.
Toxicol Sci, 2014/3;138(1):234-48.
Kakiuchi-Kiyota S[1], Koza-Taylor PH, Mantena SR, Nelms LF, Enayetallah AE, Hollingshead BD, Burdick AD, Reed LA, Warneke JA, Whiteley LO, Ryan AM, Mathialagan N
Affiliations
PMID: 24336348DOI: 10.1093/toxsci/kft278
Impact factor: 4.109
Abstract
Development of LNA gapmers, antisense oligonucleotides used for efficient inhibition of target RNA expression, is limited by non-target mediated hepatotoxicity issues. In the present study, we investigated hepatic transcription profiles of mice administered non-toxic and toxic LNA gapmers. After repeated administration, a toxic LNA gapmer (TS-2), but not a non-toxic LNA gapmer (NTS-1), caused hepatocyte necrosis and increased serum alanine aminotransferase levels. Microarray data revealed that, in addition to gene expression patterns consistent with hepatotoxicity, 17 genes in the clathrin-mediated endocytosis (CME) pathway were altered in the TS-2 group. TS-2 significantly down-regulated myosin 1E (Myo1E), which is involved in release of clathrin-coated pits from plasma membranes. To map the earliest transcription changes associated with LNA gapmer-induced hepatotoxicity, a second microarray analysis was performed using NTS-1, TS-2, and a severely toxic LNA gapmer (HTS-3) at 8, 16, and 72 h following a single administration in mice. The only histopathological change observed was minor hepatic hypertrophy in all LNA groups across time points. NTS-1, but not 2 toxic LNA gapmers, increased immune response genes at 8 and 16 h but not at 72 h. TS-2 significantly perturbed the CME pathway only at 72 h, while Myo1E levels were decreased at all time points. In contrast, HTS-3 modulated DNA damage pathway genes at 8 and 16 h and also modulated the CME pathway genes (but not Myo1E) at 16 h. Our results may suggest that different LNAs modulate distinct transcriptional genes and pathways contributing to non-target mediated hepatotoxicity in mice.
Keywords: LNA gapmers; antisense oligonucleotide; clathrin-mediated endocytosis; hepatotoxicity; microarray analysis
MeSH terms
Animals; Chemical and Drug Induced Liver Injury; Clathrin; Endocytosis; Gene Expression Profiling; Injections, Subcutaneous; Liver; Male; Mice; Mice, Inbred Strains; Molecular Sequence Data; Oligonucleotides; Oligonucleotides, Antisense; Transcriptome
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