Antisense oligonucleotides (ASOs) were first discovered to influence RNA processing and modulate protein expression over two decades ago; however, progress translating these agents into the clinic has been hampered by inadequate target engagement, insufficient biological activity, and off-target toxic effects. Over the years, novel chemical modifications of ASOs have been employed to address these issues. These modifications, in combination with elucidation of the mechanism of action of ASOs and improved clinical trial design, have provided momentum for the translation of ASO-based strategies into therapies. Many neurological conditions lack an effective treatment; however, as research progressively disentangles the pathogenic mechanisms of these diseases, they provide an ideal platform to test ASO-based strategies. This steady progress reached a pinnacle in the past few years with approvals of ASOs for the treatment of spinal muscular atrophy and Duchenne muscular dystrophy, which represent landmarks in a field in which disease-modifying therapies were virtually non-existent. With the rapid development of improved next-generation ASOs toward clinical application, this technology now holds the potential to have a dramatic effect on the treatment of many neurological conditions in the near future.

中文翻译：

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反义寡核苷酸：治疗神经系统疾病的下一个前沿领域。

二十多年前，反义寡核苷酸（ASO）首次被发现影响RNA加工并调节蛋白质表达。然而，由于靶标参与不足，生物学活性不足和脱靶毒性作用，阻碍了将这些药物转入临床的进展。多年来，已经采用了ASO的新型化学修饰来解决这些问题。这些修改，加上对ASO作用机理的阐明和改进的临床试验设计，为将基于ASO的策略转化为疗法提供了动力。许多神经系统疾病缺乏有效的治疗方法。但是，随着研究逐渐弄清这些疾病的致病机制，它们为测试基于ASO的策略提供了理想的平台。在过去的几年中，这种稳定的进展达到了顶峰，这是因为ASO被批准用于治疗脊髓性肌萎缩症和Duchenne肌营养不良症，这在实际上不存在任何可改变疾病的疗法的领域中具有里程碑意义。随着改进的下一代ASO向临床应用的迅速发展，该技术现在具有在不久的将来对许多神经系统疾病的治疗产生巨大影响的潜力。