Unveiling sequence-agnostic mixed-chemical modification patterns for splice-switching oligonucleotides using the NATURA platform
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 oligonucleotid...
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| Language: | English |
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253124003093 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Tommaso Tabaglio |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-75a4175b41164e3cbbb3057c3e6c2b04 |
| institution | Kabale University |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-75a4175b41164e3cbbb3057c3e6c2b042025-01-29T05:00:31ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-03-01361102422Unveiling sequence-agnostic mixed-chemical modification patterns for splice-switching oligonucleotides using the NATURA platformTommaso Tabaglio0Taniya Agarwal1Wei Yuan Cher2Jin Rong Ow3Ah Keng Chew4Priscila Yun Qian Sun5Raja Sekhar Reddy Gurrampati6Hongfang Lu7Praveena Naidu8Hong Kai Ng9Xavier Le Guezennec10Shi Yan Ng11Manikandan Lakshmanan12Ernesto Guccione13Keng Boon Wee14Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Corresponding author: Tommaso Tabaglio, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore.Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeInstitute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, SingaporeCenter 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; Corresponding author: Guccione Ernesto, 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.Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Corresponding author: Keng Boon Wee, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore.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.http://www.sciencedirect.com/science/article/pii/S2162253124003093MT: Oligonucleotides: Therapies and Applicationsantisense oligonucleotidesnucleic acid therapeuticsreporter systemnucleic acid chemical modificationsmixmers |
| spellingShingle | 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 Unveiling sequence-agnostic mixed-chemical modification patterns for splice-switching oligonucleotides using the NATURA platform Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications antisense oligonucleotides nucleic acid therapeutics reporter system nucleic acid chemical modifications mixmers |
| title | Unveiling sequence-agnostic mixed-chemical modification patterns for splice-switching oligonucleotides using the NATURA platform |
| title_full | Unveiling sequence-agnostic mixed-chemical modification patterns for splice-switching oligonucleotides using the NATURA platform |
| title_fullStr | Unveiling sequence-agnostic mixed-chemical modification patterns for splice-switching oligonucleotides using the NATURA platform |
| title_full_unstemmed | Unveiling sequence-agnostic mixed-chemical modification patterns for splice-switching oligonucleotides using the NATURA platform |
| title_short | Unveiling sequence-agnostic mixed-chemical modification patterns for splice-switching oligonucleotides using the NATURA platform |
| title_sort | unveiling sequence agnostic mixed chemical modification patterns for splice switching oligonucleotides using the natura platform |
| topic | MT: Oligonucleotides: Therapies and Applications antisense oligonucleotides nucleic acid therapeutics reporter system nucleic acid chemical modifications mixmers |
| url | http://www.sciencedirect.com/science/article/pii/S2162253124003093 |
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