NDLI: Ribonuclease H1-dependent hepatotoxicity caused by locked nucleic acid-modified gapmer antisense oligonucleotides

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Ribonuclease H1-dependent hepatotoxicity caused by locked nucleic acid-modified gapmer antisense oligonucleotides

Content Provider	Semantic Scholar
Author	Kasuya, Takeshi Hori, Shin-ichiro Watanabe, Ayahisa Nakajima, Mado Gahara, Yoshinari Rokushima, Masatomo Yanagimoto, Toru Kugimiya, Akira
Copyright Year	2016
Abstract	Gapmer antisense oligonucleotides cleave target RNA effectively in vivo, and is considered as promising therapeutics. Especially, gapmers modified with locked nucleic acid (LNA) shows potent knockdown activity; however, they also cause hepatotoxic side effects. For developing safe and effective gapmer drugs, a deeper understanding of the mechanisms of hepatotoxicity is required. Here, we investigated the cause of hepatotoxicity derived from LNA-modified gapmers. Chemical modification of gapmer's gap region completely suppressed both knockdown activity and hepatotoxicity, indicating that the root cause of hepatotoxicity is related to intracellular gapmer activity. Gene silencing of hepatic ribonuclease H1 (RNaseH1), which catalyses gapmer-mediated RNA knockdown, strongly supressed hepatotoxic effects. Small interfering RNA (siRNA)-mediated knockdown of a target mRNA did not result in any hepatotoxic effects, while the gapmer targeting the same position on mRNA as does the siRNA showed acute toxicity. Microarray analysis revealed that several pre-mRNAs containing a sequence similar to the gapmer target were also knocked down. These results suggest that hepatotoxicity of LNA gapmer is caused by RNAseH1 activity, presumably because of off-target cleavage of RNAs inside nuclei.
Starting Page	259
Ending Page	293
Page Count	35
File Format	PDF HTM / HTML
PubMed reference number	27461380v1
Alternate Webpage(s)	https://doi.org/10.1038/srep30377
DOI	10.1038/srep30377
Journal	Scientific reports
Volume Number	6
Language	English
Access Restriction	Open
Subject Keyword	Adverse reaction to drug Antisense Oligonucleotides Catalysis Chemical and Drug Induced Liver Injury Gene Silencing Histamine H1 Antagonists Non-Small Cell Lung Carcinoma Nucleic Acids RNA RNA, Small Interfering Ribonuclease T1 Ribonucleases Therapeutic procedure antisense therapy cellular targeting latent Orf73 antigen, human herpesvirus 8 locked nucleic acid
Content Type	Text
Resource Type	Article

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