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

被引：0

作者：

Tabaglio, Tommaso ^{[1
]}

Agarwal, Taniya ^{[1
]}

Cher, Wei Yuan ^{[1
]}

Ow, Jin Rong ^{[1
]}

Chew, Ah Keng ^{[1
]}

Sun, Priscila Yun Qian ^{[1
]}

Gurrampati, Raja Sekhar Reddy ^{[1
]}

Lu, Hongfang ^{[1
]}

Naidu, Praveena ^{[1
]}

Ng, Hong Kai ^{[1
]}

Le Guezennec, Xavier ^{[1
]}

Ng, Shi Yan ^{[1
]}

Lakshmanan, Manikandan ^{[1
]}

Guccione, Ernesto ^{[2
]}

Wee, Keng Boon ^{[1
]}

机构：

[1] ASTAR, Inst Mol & Cell Biol IMCB, Singapore, Singapore

[2] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Ctr OncoGen & Innovat Therapeut COGIT, Ctr Therapeut Discovery,Dept Oncol Sci & Pharmacol, New York, NY 10029 USA

来源：

MOLECULAR THERAPY NUCLEIC ACIDS | 2025年 / 36卷 / 01期

关键词：

ANTISENSE OLIGONUCLEOTIDES; NUSINERSEN; DESIGN; RNA;

D O I：

10.1016/j.omtn.2024.102422

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：16