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

IF 6.5 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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引用次数: 0

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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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.