Targeting RNA splicing for disease therapy.
Targeting RNA splicing for disease therapy.
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DOI：
10.1002/wrna.1158
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发表时间：
2013-05
影响因子：
7.3
通讯作者：
Hastings, Michelle L.
中科院分区：
文献类型：
--
作者：
Havens, Mallory A.;Duelli, Dominik M.;Hastings, Michelle L.
前信使RNA剪接成成熟信使RNA是高等真核生物中大多数基因表达的重要步骤。这个过程中的缺陷通常会影响细胞功能，并可能产生病理后果。许多人类遗传疾病是由导致剪接缺陷的突变引起的。此外，许多疾病与不归因于明显突变的剪接缺陷相关。直接靶向剪接以纠正疾病相关的异常剪接是一种合乎逻辑的治疗方法。剪接是疾病治疗的有利干预点，因为它是基因表达的早期步骤，并且不会改变基因组。在开发用于治疗的操纵剪接的方法方面已经取得了重大进展。剪接可以用许多工具操纵，包括反义寡核苷酸、修饰的小核RNA（snRNA）、反式剪接和小分子化合物，所有这些都已用于增加特定的可变剪接同种型或校正由改变剪接的基因突变引起的异常基因表达。在这里，我们描述了疾病状态中的临床相关剪接缺陷，目前用于靶向和改变剪接的工具，使用剪接调节方法靶向的特定突变和疾病，以及新兴的治疗方法。
Splicing of pre-messenger RNA into mature messenger RNA is an essential step for expression of most genes in higher eukaryotes. Defects in this process typically affect cellular function and can have pathological consequences. Many human genetic diseases are caused by mutations that cause splicing defects. Furthermore, a number of diseases are associated with splicing defects that are not attributed to overt mutations. Targeting splicing directly to correct disease-associated aberrant splicing is a logical approach to therapy. Splicing is a favorable intervention point for disease therapeutics, because it is an early step in gene expression and does not alter the genome. Significant advances have been made in the development of approaches to manipulate splicing for therapy. Splicing can be manipulated with a number of tools including antisense oligonucleotides, modified small nuclear RNAs (snRNAs), trans-splicing, and small molecule compounds, all of which have been used to increase specific alternatively spliced isoforms or to correct aberrant gene expression resulting from gene mutations that alter splicing. Here we describe clinically relevant splicing defects in disease states, the current tools used to target and alter splicing, specific mutations and diseases that are being targeted using splice-modulating approaches, and emerging therapeutics.
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