Antisense oligonucleotides (ASOs) are classified into gapmer and non-gapmer types according to their chemical modification pattern and mechanism of action. Although gapmer ASOs effectively reduce target RNA expression through intracellular RNase H1, high-affinity gapmer ASOs also have hepatotoxic potential. Non-gapmer ASOs, which are mainly used for pre-mRNA splicing regulation or functional inhibition of microRNA through their steric effects, are also able to inhibit target RNA expression using nonsense-mediated decay. However, it was unknown if they induce high knockdown activity without showing hepatotoxicity. In this study, we investigated the modification pattern of non-gapmer ASOs and show that they have comparable knockdown potential if they have an appropriate melting temperature (Tm) range. We also demonstrated that non-gapmer ASOs show high knockdown effects without inducing hepatotoxicity in the mouse liver. These results indicated that non-gapmer ASOs have the potential to become an alternative inhibitor of target expression with a lower risk of hepatotoxicity.

中文翻译：

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非Gapmer反义寡核苷酸引起的RNA还原和肝毒性潜力。

反义寡核苷酸（ASO）根据其化学修饰方式和作用机理分为gapmer和非gapmer类型。虽然gapmer ASO通过细胞内RNase H1有效降低靶RNA的表达，但高亲和力gapmer ASO也具有肝毒性的潜力。非gapmer ASO主要通过其空间效应用于mRNA的剪接前调控或对microRNA的功能抑制，也可以使用无义介导的衰变抑制靶RNA的表达。但是，尚不清楚它们是否诱导高敲除活性而不显示出肝毒性。在这项研究中，我们研究了非gapmer ASO的修饰模式，并表明，如果它们具有合适的熔化温度（Tm）范围，它们具有可比的击倒潜力。我们还证明了，非gapmer ASOs在不引起小鼠肝脏肝毒性的情况下显示出高的敲低效应。这些结果表明，非gapmer ASOs可能成为具有较低肝毒性风险的靶标表达的替代抑制剂。