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In Vitro Assessment of the Hepatotoxicity Potential of Therapeutic Oligonucleotides

  • Sabine SewingEmail author
  • Tanja Minz
  • Franziska Boess
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 2036)

Abstract

The mechanisms of antisense oligonucleotide-induced liver toxicity are still poorly understood. Assessment of the hepatic safety profile is currently mostly investigated directly in rodent studies. A predictive preclinical in vitro model that is capturing liver liabilities of antisense oligonucleotides can be of great help to be used as a first filter in the screening process of therapeutic oligonucleotides. We describe here an in vitro cytotoxicity assay using freshly isolated mouse hepatocytes or cryopreserved human hepatocytes that recapitulates the hepatotoxic profile of antisense oligonucleotides previously observed in rodents and can be used for the prioritization of molecules prior to in vivo testing.

Key words

Antisense oligonucleotide In vitro hepatotoxicity Liver perfusion Cytotoxicity Hepatocytes 3R 

Notes

Acknowledgments

We thank E. Durr and N. Schaub for their excellent support.

References

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    Frazier KS (2015) Antisense oligonucleotide therapies: the promise and the challenges from a toxicologic pathologist’s perspective. Toxicol Pathol 43:78–89CrossRefGoogle Scholar
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    Burdick AD, Sciabola S, Mantena SR et al (2014) Sequence motifs associated with hepatotoxicity of locked nucleic acid-modified antisense oligonucleotides. Nucleic Acid Res 42:4882–4891CrossRefGoogle Scholar
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    Stanton R, Sciabola S, Salatto C et al (2012) Chemical modification study of antisense gapmers. Nucleic Acid Ther 22:344–359CrossRefGoogle Scholar
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    Sewing S, Boess F, Moisan A et al (2016) Establishment of a predictive in vitro assay for assessment of the hepatotoxic potential of oligonucleotide drugs. PLoS One 11:e0159431CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Roche Pharma Research and Early Development, Pharmaceutical Sciences (PS)Roche Innovation Center BaselBaselSwitzerland

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