From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies.
From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies.
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DOI：
10.3390/biomedicines9050550
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发表时间：
2021-05-14
期刊：
影响因子：
4.7
通讯作者：
Morais P
中科院分区：
文献类型：
--
作者：
Adachi H;Hengesbach M;Yu YT;Morais P
治疗性寡核苷酸通过沃森-克里克互补性与靶RNA相互作用，影响RNA加工反应，如mRNA降解、前体mRNA剪接或mRNA翻译。自从几十年前提出以来，已有几种药物被批准用于临床，以纠正基因突变。已经出现了三种类型的作用机制（MoA）：由短嵌合反义寡核苷酸（gapmers）指导的RNA酶H依赖性mRNA降解，通过剪接调节寡核苷酸纠正剪接缺陷，以及通过短干扰RNA（siRNA）干扰基因表达。这些基于反义的机制可以以基因特异性的方式解决几种遗传疾病，主要是通过基因下调（gapmers和siRNA）或剪接缺陷校正（外显子跳跃寡核苷酸）。尽管如此，单核苷酸水平的修复仍然面临挑战。表转录组学和RNA修饰的新兴领域显示了在利用内源性表达的RNA加工机制的同时，以高特异性重新编码转录组和修复基因突变的巨大可能性。其中一些技术已被提议作为基于CRISPR的技术的替代方案，其中外源基因编辑机制需要在人类细胞中传递和表达，以产生永久性（DNA）变化，其后果未知。在此，我们回顾了目前FDA批准的反义MoA（强调一些促成其成功的技术）和三种基于转录后RNA修饰的具有治疗潜力的新模式，包括阿达尔（腺苷脱氨酶作用于RNA）介导的RNA编辑，靶向假尿苷化和2′-O-甲基化。
Therapeutic oligonucleotides interact with a target RNA via Watson-Crick complementarity, affecting RNA-processing reactions such as mRNA degradation, pre-mRNA splicing, or mRNA translation. Since they were proposed decades ago, several have been approved for clinical use to correct genetic mutations. Three types of mechanisms of action (MoA) have emerged: RNase H-dependent degradation of mRNA directed by short chimeric antisense oligonucleotides (gapmers), correction of splicing defects via splice-modulation oligonucleotides, and interference of gene expression via short interfering RNAs (siRNAs). These antisense-based mechanisms can tackle several genetic disorders in a gene-specific manner, primarily by gene downregulation (gapmers and siRNAs) or splicing defects correction (exon-skipping oligos). Still, the challenge remains for the repair at the single-nucleotide level. The emerging field of epitranscriptomics and RNA modifications shows the enormous possibilities for recoding the transcriptome and repairing genetic mutations with high specificity while harnessing endogenously expressed RNA processing machinery. Some of these techniques have been proposed as alternatives to CRISPR-based technologies, where the exogenous gene-editing machinery needs to be delivered and expressed in the human cells to generate permanent (DNA) changes with unknown consequences. Here, we review the current FDA-approved antisense MoA (emphasizing some enabling technologies that contributed to their success) and three novel modalities based on post-transcriptional RNA modifications with therapeutic potential, including ADAR (Adenosine deaminases acting on RNA)-mediated RNA editing, targeted pseudouridylation, and 2′-O-methylation.
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影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
82.9
作者：
Cideciyan AV;Jacobson SG;Ho AC;Garafalo AV;Roman AJ;Sumaroka A;Krishnan AK;Swider M;Schwartz MR;Girach A
通讯作者：
Girach A
影响因子：
14.9
作者：
Abou Assi H;Rangadurai AK;Shi H;Liu B;Clay MC;Erharter K;Kreutz C;Holley CL;Al-Hashimi HM
通讯作者：
Al-Hashimi HM
影响因子：
7.8
作者：
Buschmann MD;Carrasco MJ;Alishetty S;Paige M;Alameh MG;Weissman D
通讯作者：
Weissman D
影响因子：
5.2
作者：
Aller, Elena;Larrieu, Lise;Millan, Jose M.
通讯作者：
Millan, Jose M.