Invention and Early History of Exon Skipping and Splice Modulation
Invention and Early History of Exon Skipping and Splice Modulation
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DOI：
10.1007/978-1-4939-8651-4_1
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发表时间：
2018-01-01
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影响因子：
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通讯作者：
Yokota, Toshifumi
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文献类型：
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作者：
Lim, Kenji Rowel Q.;Yokota, Toshifumi
自1977年发现以来，人们对RNA剪接及其如何在人类发育、功能，尤其是疾病中发挥核心作用了解甚多。RNA剪接缺陷至少占所有遗传疾病的10%，随着非编码基因组区域对疾病贡献的更多信息被发现，这一数字预计会增加。通过使用反义寡核苷酸（AOs）进行剪接调制已成为治疗这些疾病的有希望的途径。事实上，最近有两种剪接开关的AOs获得了美国食品和药物管理局的批准：用于治疗杜氏肌营养不良的eteplirsen （Exondys 51）和用于治疗脊髓性肌萎缩的nusinersen （Spinraza）。它们分别通过外显子跳跃和外显子包含起作用。在本章中，我们讨论了基于ao的剪接调制疗法的早期发展-它的发明，第一次应用，以及它演变成我们现在熟悉的方法。我们给出了一个更广泛的外显子跳跃的历史，特别是，因为它是剪接调制方法给出了最关注在这本书。
Since its discovery in 1977, much has been known about RNA splicing and how it plays a central role in human development, function, and, notably, disease. Defects in RNA splicing account for at least 10% of all genetic disorders, with the number expected to increase as more information is uncovered on the contribution of noncoding genomic regions to disease. Splice modulation through the use of antisense oligonucleotides (AOs) has emerged as a promising avenue for the treatment of these disorders. In fact, two splice-switching AOs have recently obtained approval from the US Food and Drug Administration: eteplirsen (Exondys 51) for Duchenne muscular dystrophy, and nusinersen (Spinraza) for spinal muscular atrophy. These work by exon skipping and exon inclusion, respectively. In this chapter, we discuss the early development of AO-based splice modulation therapy-its invention, first applications, and its evolution into the approach we are now familiar with. We give a more extensive history of exon skipping in particular, as it is the splice modulation approach given the most focus in this book.