title: Mutagenesis by an antisense oligonucleotide and its degradation product.
abstract: The European Medicines Agency has expressed concern regarding (1) the potential for antisense oligonucleotide (ASO) therapeutics to induce sequence-specific mutation at genomic DNA and (2) the capability of ASO degradation products (nucleotide analogues) to incorporate into newly synthesized genomic DNA via DNA polymerase and cause mutation if base pairing occurs with reduced fidelity. Treating human lymphoblastoid cells with a biologically active antisense molecule induced sequence-specific mutation within genomic DNA over fourfold, in a system where RAD51 protein expression was induced. This finding has implications for ASO therapeutics with individuals with an induced DNA damage response, such as cancer patients. Furthermore, a phosphorothioate nucleotide analogue potently induced mutation at genomic DNA two orders of magnitude above control. This study shows that a biologically active ASO molecule can induce heritable sequence alterations, and if degraded, its respective analogue may incorporate into genomic DNA with mutagenic consequences.
authors.affiliation: Biomolecular Medicine, Imperial College, London SW7 2AZ, United Kingdom.
authors.forename: Reshat
authors.initials: R
authors.lastname: Reshat
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Priestley
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Gooderham
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071096:ADAMTS Proteins; D001483:Base Sequence; D001711:Biotransformation; D002460:Cell Line; D004249:DNA Damage; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009152:Mutagenicity Tests; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000378:metabolism / Q000633:toxicity*; D054735:Phosphorothioate Oligonucleotides / Q000378:metabolism / Q000633:toxicity*; D011348:Procollagen N-Endopeptidase / Q000235:genetics / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D007041:Hypoxanthine Phosphoribosyltransferase; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C434951:ADAMTS3 protein, human; D011348:Procollagen N-Endopeptidase