Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts.

Abstract:

:High affinity antisense oligonucleotides (ASOs) containing bicylic modifications (BNA) such as locked nucleic acid (LNA) designed to induce target RNA cleavage have been shown to have enhanced potency along with a higher propensity to cause hepatotoxicity. In order to understand the mechanism of this hepatotoxicity, transcriptional profiles were collected from the livers of mice treated with a panel of highly efficacious hepatotoxic or non-hepatotoxic LNA ASOs. We observed highly selective transcript knockdown in mice treated with non-hepatotoxic LNA ASOs, while the levels of many unintended transcripts were reduced in mice treated with hepatotoxic LNA ASOs. This transcriptional signature was concurrent with on-target RNA reduction and preceded transaminitis. Remarkably, the mRNA transcripts commonly reduced by toxic LNA ASOs were generally not strongly associated with any particular biological process, cellular component or functional group. However, they tended to have much longer pre-mRNA transcripts. We also demonstrate that the off-target RNA knockdown and hepatotoxicity is attenuated by RNase H1 knockdown, and that this effect can be generalized to high affinity modifications beyond LNA. This suggests that for a certain set of ASOs containing high affinity modifications such as LNA, hepatotoxicity can occur as a result of unintended off-target RNase H1 dependent RNA degradation.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Burel SA,Hart CE,Cauntay P,Hsiao J,Machemer T,Katz M,Watt A,Bui HH,Younis H,Sabripour M,Freier SM,Hung G,Dan A,Prakash TP,Seth PP,Swayze EE,Bennett CF,Crooke ST,Henry SP

doi

10.1093/nar/gkv1210

subject

Has Abstract

pub_date

2016-03-18 00:00:00

pages

2093-109

issue

5

eissn

0305-1048

issn

1362-4962

pii

gkv1210

journal_volume

44

pub_type

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