RNA救援——通过社区科学设计剪接调节的反义寡核苷酸。

IF 4.2 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
RNA Pub Date : 2025-05-27 DOI:10.1261/rna.080288.124
Victor Tse, Martin Guiterrez, Jill Townley, Jonathan Romano, Jennifer Pearl, Guillermo Chacaltana, Eterna Players, Rhiju Das, Jeremy Sanford, Michael Stone
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引用次数: 0

摘要

剪接调节反义寡核苷酸(ASOs)是基于精确rna的药物,正在成为治疗人类疾病的一种确定的方式。先前,我们报道了ASOs的发现,该ASOs靶向一种新的假定的内含子RNA结构,以挽救导致a型血友病的F8外显子16的多种致病性变异体的剪接。然而,发现剪接调节ASOs的传统方法既费力又昂贵。在这里,我们描述了一种整合数据驱动的RNA结构预测和社区科学的新方法来发现剪接调节的aso。使用F8外显子16剪接缺陷致病变异作为模型,我们发现在Eterna OpenASO挑战中设计的25%的得分最高的分子对增强外显子16剪接具有统计学显著的影响。此外,我们发现由Eterna玩家设计的ASOs的独特组合可以增加剪接缺陷外显子16变体的包含。总之,我们的数据表明,来自公民科学家社区的众包设计可能会加速和补充传统途径,以发现具有治疗人类疾病潜力的剪接调节aso。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
OpenASO: RNA Rescue - designing splice-modulating antisense oligonucleotides through community science.

Splice-modulating antisense oligonucleotides (ASOs) are precision RNA-based drugs that are becoming an established modality to treat human disease. Previously, we reported the discovery of ASOs that target a novel, putative intronic RNA structure to rescue splicing of multiple pathogenic variants of F8 exon 16 that cause hemophilia A. However, the conventional approach to discovering splice-modulating ASOs is both laborious and expensive. Here, we describe a novel approach that integrates data-driven RNA structure prediction and community science to discover splice-modulating ASOs. Using a splicing-deficient pathogenic variant of F8 exon 16 as a model, we show that 25% of the top-scoring molecules designed in the Eterna OpenASO challenge have a statistically significant impact on enhancing exon 16 splicing. Additionally, we show that a distinct combination of ASOs designed by Eterna players can additively enhance the inclusion of the splicing-deficient exon 16 variant. Together, our data suggests that crowdsourcing designs from a community of citizen scientists may accelerate and complement traditional avenues for the discovery of splice-modulating ASOs with potential to treat human disease.

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来源期刊
RNA
RNA 生物-生化与分子生物学
CiteScore
8.30
自引率
2.20%
发文量
101
审稿时长
2.6 months
期刊介绍: RNA is a monthly journal which provides rapid publication of significant original research in all areas of RNA structure and function in eukaryotic, prokaryotic, and viral systems. It covers a broad range of subjects in RNA research, including: structural analysis by biochemical or biophysical means; mRNA structure, function and biogenesis; alternative processing: cis-acting elements and trans-acting factors; ribosome structure and function; translational control; RNA catalysis; tRNA structure, function, biogenesis and identity; RNA editing; rRNA structure, function and biogenesis; RNA transport and localization; regulatory RNAs; large and small RNP structure, function and biogenesis; viral RNA metabolism; RNA stability and turnover; in vitro evolution; and RNA chemistry.
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