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使用NATURA平台揭示用于剪接转换寡核苷酸的序列无关混合化学修饰模式。

Unveiling sequence-agnostic mixed-chemical modification patterns for splice-switching oligonucleotides using the NATURA platform.

作者信息

Tabaglio Tommaso, Agarwal Taniya, Cher Wei Yuan, Ow Jin Rong, Chew Ah Keng, Sun Priscila Yun Qian, Reddy Gurrampati Raja Sekhar, Lu Hongfang, Naidu Praveena, Ng Hong Kai, Le Guezennec Xavier, Ng Shi Yan, Lakshmanan Manikandan, Guccione Ernesto, Wee Keng Boon

机构信息

Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore.

Center for OncoGenomics and Innovative Therapeutics (COGIT), Center for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

出版信息

Mol Ther Nucleic Acids. 2025 Jan 7;36(1):102422. doi: 10.1016/j.omtn.2024.102422. eCollection 2025 Mar 11.

DOI:10.1016/j.omtn.2024.102422
PMID:39926316
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11803158/
Abstract

Chemical optimization of ribose has significantly advanced nucleic acid therapeutics (NATs) by improving the stability, specificity, and safety of therapies like small interfering RNAs, CRISPR-Cas9 guide RNAs, and GAPmers. Recent research has extended this approach to splice-switching oligonucleotides (SSOs), which target splicing events. Our study identifies a set of mixed-modification patterns-combining 2'-O-Methyl, 2'-MethOxyEthyl, 2'-Locked Nucleic Acid, and 2'-Constrained Ethyl ribose moieties (2'OMe, 2'MOE, LNA, and cET)-that enhance SSO potency. We term this strategy lateral mixed positional configuration, which improves SSO efficacy across various sequences and could reduce the trial-and-error process in SSO development. This advancement is supported by NAT Unlabeled Reporter Assay (NATURA), a novel platform for high-throughput quantification of NATs' functional delivery and potency. NATURA uses a reporter gene system and a comprehensive sequence library to test modifications and delivery methods, validated in a transgenic mouse model. This approach aims to accelerate NAT development and address challenges in delivering these therapies to patients.

摘要

核糖的化学优化通过提高小干扰RNA、CRISPR-Cas9引导RNA和GAPmer等疗法的稳定性、特异性和安全性，显著推动了核酸疗法（NATs）的发展。最近的研究已将这种方法扩展到针对剪接事件的剪接转换寡核苷酸（SSO）。我们的研究确定了一组混合修饰模式，即结合2'-O-甲基、2'-甲氧基乙基、2'-锁核酸和2'-约束乙基核糖部分（2'OMe、2'MOE、LNA和cET），可提高SSO的效力。我们将此策略称为横向混合位置构型，它可提高各种序列的SSO功效，并可能减少SSO开发中的反复试验过程。这一进展得到了NAT未标记报告基因测定法（NATURA）的支持，NATURA是一个用于高通量定量NATs功能递送和效力的新型平台。NATURA使用报告基因系统和综合序列文库来测试修饰和递送方法，并在转基因小鼠模型中得到验证。这种方法旨在加速NAT的开发，并应对将这些疗法递送给患者时面临的挑战。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f8c/11803158/e8f32507a548/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f8c/11803158/a3d84e0b0b77/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f8c/11803158/00cc1ad7c9dd/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f8c/11803158/14cb695b7f8d/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f8c/11803158/02b9ffa9c328/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f8c/11803158/e8f32507a548/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f8c/11803158/a3d84e0b0b77/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f8c/11803158/00cc1ad7c9dd/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f8c/11803158/14cb695b7f8d/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f8c/11803158/02b9ffa9c328/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f8c/11803158/e8f32507a548/gr4.jpg

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Biomedicines. 2023 Nov 16;11(11):3071. doi: 10.3390/biomedicines11113071.
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A framework for individualized splice-switching oligonucleotide therapy.个体化剪接寡核苷酸治疗的框架。
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