Dysregulation of RNA splicing causes many diseases and disorders. Several therapeutic approaches have been developed to correct aberrant alternative splicing events for the treatment of cancers and hereditary diseases, including gene therapy and redirecting splicing, using small molecules or splice switching oligonucleotides (SSO). Significant advances in the chemistry and pharmacology of nucleic acid have led to the development of clinically approved SSO drugs for the treatment of spinal muscular dystrophy and Duchenne muscular dystrophy (DMD). In this review, we discuss the mechanisms of SSO action with emphasis on “less common” approaches to modulate alternative splicing, including bipartite and bifunctional SSO, oligonucleotide decoys for splice factors and SSO-mediated mRNA degradation via AS-NMD and NGD pathways. We briefly discuss the current progress and future perspectives of SSO therapy for rare and ultrarare diseases.

中文翻译：

---

寡核苷酸对 RNA 剪接的调节：作用机制和治疗意义

RNA 剪接的失调会导致许多疾病和紊乱。已经开发了几种治疗方法来纠正异常选择性剪接事件以治疗癌症和遗传性疾病，包括基因治疗和重定向剪接，使用小分子或剪接转换寡核苷酸 (SSO)。核酸化学和药理学的重大进展导致临床批准的用于治疗脊髓性肌营养不良症和杜氏肌营养不良症 (DMD) 的 SSO 药物的开发。在这篇综述中，我们讨论了 SSO 作用的机制，重点是调节可变剪接的“不太常见”方法，包括二分和双功能 SSO、剪接因子的寡核苷酸诱饵和 SSO 介导的 mRNA 降解。AS-NMD 和 NGD 途径。我们简要讨论 SSO 治疗罕见和超罕见疾病的当前进展和未来前景。