Department of Pediatrics, Mount Sinai Hospital, New York, NY 10029, USA.
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Mol Cells. 2023 Jan 31;46(1):10-20. doi: 10.14348/molcells.2023.2172. Epub 2023 Jan 15.
Antisense oligonucleotide (ASO) technology has become an attractive therapeutic modality for various diseases, including Mendelian disorders. ASOs can modulate the expression of a target gene by promoting mRNA degradation or changing pre-mRNA splicing, nonsense-mediated mRNA decay, or translation. Advances in medicinal chemistry and a deeper understanding of post-transcriptional mechanisms have led to the approval of several ASO drugs for diseases that had long lacked therapeutic options. For instance, an ASO drug called nusinersen became the first approved drug for spinal muscular atrophy, improving survival and the overall disease course. Mutations in the cystic fibrosis transmembrane conductance regulator () gene cause cystic fibrosis (CF). Although Trikafta and other CFTR-modulation therapies benefit most CF patients, there is a significant unmet therapeutic need for a subset of CF patients. In this review, we introduce ASO therapies and their mechanisms of action, describe the opportunities and challenges for ASO therapeutics for CF, and discuss the current state and prospects of ASO therapies for CF.
反义寡核苷酸（ASO）技术已成为治疗各种疾病的一种有吸引力的治疗方式，包括孟德尔疾病。ASO 可以通过促进 mRNA 降解或改变前体 mRNA 剪接、无义介导的 mRNA 衰变或翻译来调节靶基因的表达。药物化学的进步和对转录后机制的深入了解导致了几种 ASO 药物的批准，用于长期缺乏治疗选择的疾病。例如，一种名为 nusinersen 的 ASO 药物成为首个获批用于脊髓性肌萎缩症的药物，改善了生存和整体疾病进程。囊性纤维化跨膜电导调节因子（CFTR）基因的突变导致囊性纤维化（CF）。虽然 Trikafta 和其他 CFTR 调节剂疗法使大多数 CF 患者受益，但仍有一部分 CF 患者存在显著的未满足的治疗需求。在这篇综述中，我们介绍了 ASO 疗法及其作用机制，描述了 ASO 疗法在 CF 中的机遇和挑战，并讨论了 CF 的 ASO 疗法的现状和前景。
