Haiwen Ruan , Dehu Dou , Jing Lu , Xia Xiao , Xinjiang Gong , Xuefeng Zhang
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Off-target toxicity may be caused by hybridization to sequences that are similar but not identical to the target, hybridization-independent sequence related, or sequence- and hybridization-independent effects. The effects may result in diminished transcript levels, decreased translation rates, or anomalous splicing, employing same molecular pathways and protein machinery as the desired on-target effects. Currently, there exists no established methodology for the systematic identification and evaluation of off-target toxicity, which may hinder the optimization of safety approaches. This review delineates significant nonclinical toxicities and clinical adverse effects by summarizing and analyzing approved oligonucleotides with their off-target assays, encompassing the limitations of nonclinical off-target effects and the potential off-target mechanisms. Plus, it discusses and emphasizes the factors that lead to the off target of ONTs, systematically offers approaches and workflows of preclinical assessments to enhance the transfer value of oligonucleotide therapies from nonclinical to clinical trials by managing unavoidable off-target effects.</div></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"35 ","pages":"Article 100254"},"PeriodicalIF":2.7000,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Off-target effects of oligonucleotides and approaches of preclinical assessments\",\"authors\":\"Haiwen Ruan , Dehu Dou , Jing Lu , Xia Xiao , Xinjiang Gong , Xuefeng Zhang\",\"doi\":\"10.1016/j.slasd.2025.100254\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Oligonucleotide-based therapies, such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), represent a class of therapeutic agents that specifically target gene transcription or translation mechanisms through sequence specificity. These pharmaceuticals exhibit significant promise in the treatment of genetic disorders, including spinal muscular atrophy, as well as malignancies, viral infections, and metabolic diseases. Nonetheless, unintended toxicity continues to pose a considerable challenge and remain a critical safety concern in the development of oligonucleotide therapeutics (ONTs). Off-target toxicity may be caused by hybridization to sequences that are similar but not identical to the target, hybridization-independent sequence related, or sequence- and hybridization-independent effects. The effects may result in diminished transcript levels, decreased translation rates, or anomalous splicing, employing same molecular pathways and protein machinery as the desired on-target effects. Currently, there exists no established methodology for the systematic identification and evaluation of off-target toxicity, which may hinder the optimization of safety approaches. This review delineates significant nonclinical toxicities and clinical adverse effects by summarizing and analyzing approved oligonucleotides with their off-target assays, encompassing the limitations of nonclinical off-target effects and the potential off-target mechanisms. Plus, it discusses and emphasizes the factors that lead to the off target of ONTs, systematically offers approaches and workflows of preclinical assessments to enhance the transfer value of oligonucleotide therapies from nonclinical to clinical trials by managing unavoidable off-target effects.</div></div>\",\"PeriodicalId\":21764,\"journal\":{\"name\":\"SLAS Discovery\",\"volume\":\"35 \",\"pages\":\"Article 100254\"},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2025-07-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"SLAS Discovery\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2472555225000474\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMICAL RESEARCH METHODS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"SLAS Discovery","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2472555225000474","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
Off-target effects of oligonucleotides and approaches of preclinical assessments
Oligonucleotide-based therapies, such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), represent a class of therapeutic agents that specifically target gene transcription or translation mechanisms through sequence specificity. These pharmaceuticals exhibit significant promise in the treatment of genetic disorders, including spinal muscular atrophy, as well as malignancies, viral infections, and metabolic diseases. Nonetheless, unintended toxicity continues to pose a considerable challenge and remain a critical safety concern in the development of oligonucleotide therapeutics (ONTs). Off-target toxicity may be caused by hybridization to sequences that are similar but not identical to the target, hybridization-independent sequence related, or sequence- and hybridization-independent effects. The effects may result in diminished transcript levels, decreased translation rates, or anomalous splicing, employing same molecular pathways and protein machinery as the desired on-target effects. Currently, there exists no established methodology for the systematic identification and evaluation of off-target toxicity, which may hinder the optimization of safety approaches. This review delineates significant nonclinical toxicities and clinical adverse effects by summarizing and analyzing approved oligonucleotides with their off-target assays, encompassing the limitations of nonclinical off-target effects and the potential off-target mechanisms. Plus, it discusses and emphasizes the factors that lead to the off target of ONTs, systematically offers approaches and workflows of preclinical assessments to enhance the transfer value of oligonucleotide therapies from nonclinical to clinical trials by managing unavoidable off-target effects.
期刊介绍:
Advancing Life Sciences R&D: SLAS Discovery reports how scientists develop and utilize novel technologies and/or approaches to provide and characterize chemical and biological tools to understand and treat human disease.
SLAS Discovery is a peer-reviewed journal that publishes scientific reports that enable and improve target validation, evaluate current drug discovery technologies, provide novel research tools, and incorporate research approaches that enhance depth of knowledge and drug discovery success.
SLAS Discovery emphasizes scientific and technical advances in target identification/validation (including chemical probes, RNA silencing, gene editing technologies); biomarker discovery; assay development; virtual, medium- or high-throughput screening (biochemical and biological, biophysical, phenotypic, toxicological, ADME); lead generation/optimization; chemical biology; and informatics (data analysis, image analysis, statistics, bio- and chemo-informatics). Review articles on target biology, new paradigms in drug discovery and advances in drug discovery technologies.
SLAS Discovery is of particular interest to those involved in analytical chemistry, applied microbiology, automation, biochemistry, bioengineering, biomedical optics, biotechnology, bioinformatics, cell biology, DNA science and technology, genetics, information technology, medicinal chemistry, molecular biology, natural products chemistry, organic chemistry, pharmacology, spectroscopy, and toxicology.
SLAS Discovery is a member of the Committee on Publication Ethics (COPE) and was published previously (1996-2016) as the Journal of Biomolecular Screening (JBS).