{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:35:56Z","timestamp":1792787756362,"version":"4.5.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP15am0301004"],"award-info":[{"award-number":["JP15am0301004"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP19am0401003"],"award-info":[{"award-number":["JP19am0401003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Currently, gapmer antisense oligonucleotide (ASO) therapeutics are under clinical development for the treatment of various diseases, including previously intractable human disorders; however, they have the potential to induce hepatotoxicity. Although several groups have reported the reduced hepatotoxicity of gapmer ASOs following chemical modifications of sugar residues or internucleotide linkages, only few studies have described nucleobase modifications to reduce hepatotoxicity. In this study, we introduced single or multiple combinations of 17 nucleobase derivatives, including four novel derivatives, into hepatotoxic locked nucleic acid gapmer ASOs and examined their effects on hepatotoxicity. The results demonstrated successful identification of chemical modifications that strongly reduced the hepatotoxicity of gapmer ASOs. This approach expands the ability to design gapmer ASOs with optimal therapeutic profiles.<\/jats:p>","DOI":"10.1093\/nar\/gkac562","type":"journal-article","created":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T13:11:18Z","timestamp":1657285878000},"page":"7224-7234","source":"Crossref","is-referenced-by-count":54,"title":["Identification of nucleobase chemical modifications that reduce the hepatotoxicity of gapmer antisense oligonucleotides"],"prefix":"10.1093","volume":"50","author":[{"given":"Tokuyuki","family":"Yoshida","sequence":"first","affiliation":[{"name":"Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences , Kawasaki, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9642-1031","authenticated-orcid":false,"given":"Kunihiko","family":"Morihiro","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Osaka University , Suita, Osaka, Japan"},{"name":"National Institutes of Biomedical Innovation,\u00a0Health and Nutrition (NIBIOHN) , Ibaraki, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Naito","sequence":"additional","affiliation":[{"name":"Database Center for Life Science (DBCLS) , 1111 Yata, Mishima, Shizuoka 411-8540, Japan"},{"name":"National Institute of Genetics , 1111 Yata, Mishima, Shizuoka 411-8540, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Mikami","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Osaka University , Suita, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1102-9795","authenticated-orcid":false,"given":"Yuuya","family":"Kasahara","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Osaka University , Suita, Osaka, Japan"},{"name":"National Institutes of Biomedical Innovation,\u00a0Health and Nutrition (NIBIOHN) , Ibaraki, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Inoue","sequence":"additional","affiliation":[{"name":"Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences , Kawasaki, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6842-6812","authenticated-orcid":false,"given":"Satoshi","family":"Obika","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Osaka University , Suita, Osaka, Japan"},{"name":"National Institutes of Biomedical Innovation,\u00a0Health and Nutrition (NIBIOHN) , Ibaraki, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"key":"2022072200034646300_B1","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.3390\/jcm9062004","article-title":"Antisense oligonucleotides: an emerging area in drug discovery and development","volume":"9","author":"Dhuri","year":"2020","journal-title":"J. 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