Antisense oligonucleotide (AON) therapies involve short strands of modified nucleotides that target RNA in a sequence‐specific manner, inducing targeted protein knockdown or restoration. Currently, 10 AON therapies have been approved in the United States and Europe. Nucleotides are chemically modified to protect AONs from degradation, enhance bioavailability and increase RNA affinity. Whereas single stranded AONs can efficiently be delivered systemically, delivery of double stranded AONs requires capsulation in lipid nanoparticles or binding to a conjugate as the uptake enhancing backbone is hidden in this conformation. With improved chemistry, delivery vehicles and conjugates, doses can be lowered, thereby reducing the risk and occurrence of side effects. AONs can be used to knockdown or restore levels of protein. Knockdown can be achieved by single stranded or double stranded AONs binding the RNA transcript and activating RNaseH‐mediated and RISC‐mediated degradation respectively. Transcript binding by AONs can also prevent translation, hence reducing protein levels. For protein restoration, single stranded AONs are used to modulate pre‐mRNA splicing and either include or skip an exon to restore protein production. Intervening at a genetic level, AONs provide therapeutic options for inherited metabolic diseases as well. This review provides an overview of the different AON approaches, with a focus on AONs developed for inborn errors of metabolism.

中文翻译：

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反义寡核苷酸疗法的机遇和挑战

反义寡核苷酸 (AON) 疗法涉及以序列特异性方式靶向 RNA 的修饰核苷酸短链，诱导靶向蛋白质敲低或恢复。目前，美国和欧洲已经批准了 10 种 AON 疗法。核苷酸经过化学修饰以保护 AON 免于降解、提高生物利用度并增加 RNA 亲和力。虽然单链 AON 可以有效地全身递送，但双链 AON 的递送需要封装在脂质纳米颗粒中或与偶联物结合，因为吸收增强骨架隐藏在这种构象中。通过改进化学、递送载体和偶联物，可以降低剂量，从而降低副作用的风险和发生。AON 可用于敲低或恢复蛋白质水平。击倒可以通过单链或双链 AONs 结合 RNA 转录物并分别激活 RNaseH 介导和 RISC 介导的降解来实现。AON 的转录本结合也可以阻止翻译，从而降低蛋白质水平。对于蛋白质恢复，单链 AON 用于调节前 mRNA 剪接，包括或跳过外显子以恢复蛋白质生产。在基因水平上进行干预，AON 也为遗传性代谢疾病提供了治疗选择。本综述概述了不同的 AON 方法，重点是为先天性代谢错误开发的 AON。从而降低蛋白质水平。对于蛋白质恢复，单链 AON 用于调节前 mRNA 剪接，包括或跳过外显子以恢复蛋白质生产。在基因水平上进行干预，AON 也为遗传性代谢疾病提供了治疗选择。本综述概述了不同的 AON 方法，重点是为先天性代谢错误开发的 AON。从而降低蛋白质水平。对于蛋白质恢复，单链 AON 用于调节前 mRNA 剪接，包括或跳过外显子以恢复蛋白质生产。在基因水平上进行干预，AON 也为遗传性代谢疾病提供了治疗选择。本综述概述了不同的 AON 方法，重点是为先天性代谢错误开发的 AON。