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Locked nucleic acid (LNA)‐based single‐stranded oligonucleotides are not genotoxic
Author(s) -
Guérard Melanie,
Andreas Zeller,
Erich Koller,
Christine Marchand,
Martina Müller B.,
Christian Weile,
Franz Schuler,
Thomas Singer,
Yann Tessier
Publication year - 2017
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.22076
Subject(s) - locked nucleic acid , oligonucleotide , nucleic acid , chemistry , mutagen , dna , microbiology and biotechnology , biochemistry , computational biology , biology
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.