title: Hepatotoxic potential of therapeutic oligonucleotides can be predicted from their sequence and modification pattern.
abstract: Antisense oligonucleotides that recruit RNase H and thereby cleave complementary messenger RNAs are being developed as therapeutics. Dose-dependent hepatic changes associated with hepatocyte necrosis and increases in serum alanine-aminotransferase levels have been observed after treatment with certain oligonucleotides. Although general mechanisms for drug-induced hepatic injury are known, the characteristics of oligonucleotides that determine their hepatotoxic potential are not well understood. Here, we present a comprehensive analysis of the hepatotoxic potential of locked nucleic acid-modified oligonucleotides in mice. We developed a random forests classifier, in which oligonucleotides are regarded as being composed of dinucleotide units, which distinguished between 206 oligonucleotides with high and low hepatotoxic potential with 80% accuracy as estimated by out-of-bag validation. In a validation set, 17 out of 23 oligonucleotides were correctly predicted (74% accuracy). In isolation, some dinucleotide units increase, and others decrease, the hepatotoxic potential of the oligonucleotides within which they are found. However, a complex interplay between all parts of an oligonucleotide can influence the hepatotoxic potential. Using the classifier, we demonstrate how an oligonucleotide with otherwise high hepatotoxic potential can be efficiently redesigned to abate hepatotoxic potential. These insights establish analysis of sequence and modification patterns as a powerful tool in the preclinical discovery process for oligonucleotide-based medicines.
authors: Department of Informatics, Santaris Pharma A/S, Hørsholm, Denmark.
authors: Peter H
authors: PH
authors: Hagedorn
authors: Victor
authors: V
authors: Yakimov
authors: Søren
authors: S
authors: Ottosen
authors: Susanne
authors: S
authors: Kammler
authors: Niels F
authors: NF
authors: Nielsen
authors: Anja M
authors: AM
authors: Høg
authors: Maj
authors: M
authors: Hedtjärn
authors: Michael
authors: M
authors: Meldgaard
authors: Marianne R
authors: MR
authors: Møller
authors: Henrik
authors: H
authors: Orum
authors: Troels
authors: T
authors: Koch
authors: Morten
authors: M
authors: Lindow
mesh_terms: D000410:Alanine Transaminase / Q000097:blood*; D000465:Algorithms; D000818:Animals; D001835:Body Weight; D015195:Drug Design; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000633:toxicity*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000138:chemical synthesis / Q000633:toxicity*; D009929:Organ Size; D054735:Phosphorothioate Oligonucleotides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000633:toxicity*; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship
chemical_list: D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; C477371:locked nucleic acid; D000410:Alanine Transaminase
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