Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA; UCSD Center for RNA Technologies and Therapeutics, University of California San Diego, La Jolla, CA, USA.
Curr Opin Genet Dev. 2024 Dec;89:102272. doi: 10.1016/j.gde.2024.102272. Epub 2024 Oct 29.
Alternative splicing (AS) plays a pivotal role in protein diversity and mRNA maturation. Programmable control of targeted AS events is of longstanding interest in RNA biology, promising correction of dysregulated splicing in disease and discovery of AS events. This review explores four main strategies for programmable splicing manipulation: (1) inhibiting splicing signals with antisense oligonucleotides (ASOs), exemplified by therapies approved by the U.S. Food and Drug Administration, (2) applying DNA-targeting clustered regularly interspaced short palindromic repeats systems to edit splicing signals, (3) using synthetic splicing factors, including synthetic proteins and ribonucleoproteins, inspired by natural RNA-binding proteins, and (4) guiding endogenous splicing machinery with bifunctional ASOs and engineered small nuclear RNAs. While ASOs remain clinically prominent, emerging technologies aim for broad, scalable, durable, and precise splicing modulation, holding promise for transformative advancements in RNA biology and therapeutic interventions.
选择性剪接 (AS) 在蛋白质多样性和 mRNA 成熟中发挥着关键作用。靶向 AS 事件的可编程控制一直是 RNA 生物学的研究热点，有望纠正疾病中失调的剪接，并发现新的 AS 事件。本综述探讨了可编程剪接操纵的四种主要策略：（1）利用反义寡核苷酸 (ASO) 抑制剪接信号，美国食品和药物管理局批准的疗法就是这方面的例子；（2）应用靶向 DNA 的簇状规则间隔短回文重复系统编辑剪接信号；（3）利用合成剪接因子，包括受天然 RNA 结合蛋白启发的合成蛋白和核糖核蛋白；（4）利用双功能 ASO 和工程小核 RNA 引导内源性剪接机制。虽然 ASO 仍然在临床上占据重要地位，但新兴技术旨在实现广泛、可扩展、持久和精确的剪接调控，有望在 RNA 生物学和治疗干预方面取得突破性进展。
