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

IF 6.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy. Nucleic Acids Pub Date : 2025-01-07 eCollection Date: 2025-03-11 DOI:10.1016/j.omtn.2024.102422

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

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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.

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揭示序列不可知的混合化学修饰模式剪接开关寡核苷酸使用自然平台。

核糖的化学优化通过提高小干扰rna、CRISPR-Cas9引导rna和GAPmers等治疗方法的稳定性、特异性和安全性，显著推进了核酸治疗（nas）。最近的研究已将这种方法扩展到剪接开关寡核苷酸（SSOs），其目标剪接事件。我们的研究确定了一组混合修饰模式-结合2'- o -甲基，2'-甲氧基乙基，2'-锁定核酸和2'-受限乙基核糖片段（2' ome, 2' moe， LNA和cET）-增强SSO效力。我们将这种策略称为横向混合位置配置，它可以提高跨各种序列的单点登录效率，并减少单点登录开发中的试错过程。这一进展得到了NAT Unlabeled Reporter Assay （NATURA）的支持，nata是一种高通量定量NAT功能传递和效价的新平台。NATURA使用报告基因系统和一个全面的序列库来测试修饰和传递方法，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，并解决向患者提供这些治疗的挑战。

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来源期刊

Molecular Therapy. Nucleic Acids MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

15.40

自引率

1.10%

发文量

336

审稿时长

20 weeks

期刊介绍： Molecular Therapy Nucleic Acids is an international, open-access journal that publishes high-quality research in nucleic-acid-based therapeutics to treat and correct genetic and acquired diseases. It is the official journal of the American Society of Gene & Cell Therapy and is built upon the success of Molecular Therapy. The journal focuses on gene- and oligonucleotide-based therapies and publishes peer-reviewed research, reviews, and commentaries. Its impact factor for 2022 is 8.8. The subject areas covered include the development of therapeutics based on nucleic acids and their derivatives, vector development for RNA-based therapeutics delivery, utilization of gene-modifying agents like Zn finger nucleases and triplex-forming oligonucleotides, pre-clinical target validation, safety and efficacy studies, and clinical trials.