title: Locked nucleic acid (LNA): Based single-stranded oligonucleotides are not genotoxic.
abstract: Over the last decade, single stranded oligonucleotides (ON) have gained increased attention as a new drug modality. Because the assessment of genotoxicity risk during early development of pharmaceuticals is essential, we evaluated the potential of locked nucleic acids (LNA)-ONs to induce DNA damage in L5178Y tk+/-cells both with the mouse lymphoma assay (MLA) and the micronucleus test (MNT). Further, the MLA was performed to assess gene and chromosome mutation over 3 and 24h (± metabolic activation). In addition, the MNT was performed to assess, in addition, a potential aneugenic liability. None of the experiments demonstrated a genotoxic effect for the five tested LNA-ONs. We further show data from four proprietary LNA-ONs tested in standard genotoxicity assays in vitro and partially in vivo, which were all negative. In addition, cellular and nuclear uptake of LNA-ONs in L5178Y tk+/-cells was demonstrated. Based on the results presented here as well as in the literature about other representatives of this class, we consider LNA-ONs as generally not DNA reactive and question whether genotoxicity testing of this class of ONs should be required. This is in line with recent recommendation made by the OSWG that extensively assessed the genotoxicity of oligonucleotides. Environ. Mol. Mutagen. 58:112-121, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Pharmaceutical Sciences, Roche Innovation Center Basel, Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Ltd, Basel, 4070, Switzerland.
authors.forename: Melanie
authors.initials: M
authors.lastname: Guérard
authors.affiliation: Pharmaceutical Sciences, Roche Innovation Center Basel, Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Ltd, Basel, 4070, Switzerland.
authors.forename: Zeller
authors.initials: Z
authors.lastname: Andreas
authors.affiliation: Pharmaceutical Sciences, Roche Innovation Center Basel, Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Ltd, Basel, 4070, Switzerland.
authors.forename: Koller
authors.initials: K
authors.lastname: Erich
authors.affiliation: Pharmaceutical Sciences, Roche Innovation Center Basel, Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Ltd, Basel, 4070, Switzerland.
authors.forename: Marchand
authors.initials: M
authors.lastname: Christine
authors.affiliation: Pharmaceutical Sciences, Roche Innovation Center Basel, Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Ltd, Basel, 4070, Switzerland.
authors.forename: Müller B
authors.initials: MB
authors.lastname: Martina
authors.affiliation: Roche Innovation Center Copenhagen A/S, Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Ltd, Hørsholm, 2970, Denmark.
authors.forename: Weile
authors.initials: W
authors.lastname: Christian
authors.affiliation: Pharmaceutical Sciences, Roche Innovation Center Basel, Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Ltd, Basel, 4070, Switzerland.
authors.forename: Schuler
authors.initials: S
authors.lastname: Franz
authors.affiliation: Pharmaceutical Sciences, Roche Innovation Center Basel, Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Ltd, Basel, 4070, Switzerland.
authors.forename: Singer
authors.initials: S
authors.lastname: Thomas
authors.affiliation: Roche Innovation Center Copenhagen A/S, Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Ltd, Hørsholm, 2970, Denmark.
authors.forename: Tessier
authors.initials: T
authors.lastname: Yann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001702:Biopharmaceutics / Q000379:methods; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D051379:Mice; D009152:Mutagenicity Tests; D009841:Oligonucleotides / Q000235:genetics / Q000633:toxicity*; D062085:RNA, Long Noncoding / Q000235:genetics
chemical_list: C557040:Malat1 long non-coding RNA, mouse; D009841:Oligonucleotides; D062085:RNA, Long Noncoding; C477371:locked nucleic acid
keywords: genotoxicity; locked nucleic acid; oligonucleotides