Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA.
Nat Rev Drug Discov. 2021 Jun;20(6):427-453. doi: 10.1038/s41573-021-00162-z. Epub 2021 Mar 24.
Antisense technology is now beginning to deliver on its promise to treat diseases by targeting RNA. Nine single-stranded antisense oligonucleotide (ASO) drugs representing four chemical classes, two mechanisms of action and four routes of administration have been approved for commercial use, including the first RNA-targeted drug to be a major commercial success, nusinersen. Although all the approved drugs are for use in patients with rare diseases, many of the ASOs in late- and middle-stage clinical development are intended to treat patients with very common diseases. ASOs in development are showing substantial improvements in potency and performance based on advances in medicinal chemistry, understanding of molecular mechanisms and targeted delivery. Moreover, the ASOs in development include additional mechanisms of action and routes of administration such as aerosol and oral formulations. Here, we describe the key technological advances that have enabled this progress and discuss recent clinical trials that illustrate the impact of these advances on the performance of ASOs in a wide range of therapeutic applications. We also consider strategic issues such as target selection and provide perspectives on the future of the field.
反义技术现在开始通过靶向 RNA 来实现治疗疾病的承诺。有九种单链反义寡核苷酸 (ASO) 药物代表了四种化学类别、两种作用机制和四种给药途径已被批准用于商业用途，其中包括第一个成为主要商业成功的 RNA 靶向药物，nusinersen。尽管所有批准的药物都是用于治疗罕见病患者，但处于后期和中期临床开发阶段的许多 ASO 旨在治疗患有非常常见疾病的患者。基于药物化学、分子机制理解和靶向递送方面的进展，开发中的 ASO 在效力和性能方面显示出了实质性的提高。此外，开发中的 ASO 还包括其他作用机制和给药途径，如气雾剂和口服制剂。在这里，我们描述了实现这一进展的关键技术进步，并讨论了最近的临床试验，这些试验说明了这些进展对 ASO 在广泛治疗应用中的性能的影响。我们还考虑了目标选择等战略问题，并对该领域的未来进行了展望。
