{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T22:25:54Z","timestamp":1781821554939,"version":"3.54.5"},"reference-count":35,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T00:00:00Z","timestamp":1748736000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T00:00:00Z","timestamp":1748736000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Nucleic Acid Therapeutics"],"published-print":{"date-parts":[[2025,6,1]]},"abstract":"<jats:p>Amido-bridged nucleic acid (AmNA) and a 2\u2032-O,4\u2032-C-spirocyclopropylene bridged nucleic acid (scpBNA) are bridged nucleic acid analogs with high binding affinity toward complementary strands along with high nuclease resistance. AmNA and scpBNA have been developed to overcome phosphorothioate modified gapmer hepatotoxicity, while the mechanism of reducing hepatotoxicity still remains unknown. Here, we found that antisense oligonucleotides (ASOs) with combination of AmNA, scpBNA, and phosphodiester (PO) bonds could significantly reduce hepatotoxicity in mice. Histopathological findings of the periportal spaces of the liver were observed only in the locked nucleic acid and AmNA-scpBNA groups, but not in the AmNA-scpBNA-PO group. Furthermore, bioinformatics and histopathological analysis revealed that the reduced hepatotoxicity might be related to mitochondrial abnormalities, such as decreased expression levels of Atp5o and Sdhb genes. Taken together, the results of this study demonstrated that AmNA, scpBNA, and PO modification are able to reduce hepatotoxicity for improving the potential of ASOs.<\/jats:p>","DOI":"10.1089\/nat.2024.0047","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T04:15:54Z","timestamp":1742962554000},"page":"114-124","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":5,"title":["Hepatotoxicity Reduction Profiles of Antisense Oligonucleotides Containing Amido-Bridged Nucleic Acid and 2\u2032-O,4\u2032-C-Spirocyclopropylene Bridged Nucleic Acid"],"prefix":"10.1177","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5855-8022","authenticated-orcid":false,"given":"Takaaki","family":"Kawanobe","sequence":"first","affiliation":[{"name":"Luxna Biotech Co., Ltd., Suita, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Asano","sequence":"additional","affiliation":[{"name":"Axcelead Drug Discovery Partners, Inc., Fujisawa, Kanagawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Kandori","sequence":"additional","affiliation":[{"name":"Axcelead Drug Discovery Partners, Inc., Fujisawa, Kanagawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masami","family":"Aoki","sequence":"additional","affiliation":[{"name":"Axcelead Drug Discovery Partners, Inc., Fujisawa, Kanagawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajaya Ram","family":"Shrestha","sequence":"additional","affiliation":[{"name":"Luxna Biotech Co., Ltd., Suita, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuo","family":"Sekiguchi","sequence":"additional","affiliation":[{"name":"Luxna Biotech Co., Ltd., Suita, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotaro","family":"Yokoyama","sequence":"additional","affiliation":[{"name":"Axcelead Drug Discovery Partners, Inc., Fujisawa, Kanagawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Axcelead Drug Discovery Partners, Inc., Fujisawa, Kanagawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Umemoto","sequence":"additional","affiliation":[{"name":"Luxna Biotech Co., Ltd., Suita, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,6,5]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw144"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3779"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.0c04928"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa299"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw112"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(97)10322-7"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1039\/a708608c"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi0485732"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2013.619"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkl1071"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1210"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.791416"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0106-2"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2022.0005"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab047"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201200506"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1039\/C5OB00242G"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2017.09.004"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1039\/C5CC02024G"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.6b02036"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-812513-7.00008-2"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks273"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25327"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2017.0709"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2014.02.014"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2008.14"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2007.01.002"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1232"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nu.16.070196.001143"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.88764"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2021.0059"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.12.010"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13679-022-00473-1"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2013.08.011"},{"key":"e_1_3_6_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.05.040"}],"container-title":["Nucleic Acid Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/nat.2024.0047","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/nat.2024.0047","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/nat.2024.0047","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T21:03:26Z","timestamp":1777669406000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/nat.2024.0047"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,1]]},"references-count":35,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,6,1]]}},"alternative-id":["10.1089\/nat.2024.0047"],"URL":"https:\/\/doi.org\/10.1089\/nat.2024.0047","relation":{},"ISSN":["2159-3337","2159-3345"],"issn-type":[{"value":"2159-3337","type":"print"},{"value":"2159-3345","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,1]]}}}