Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kawasaki, Kanagawa, Japan.
Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Nucleic Acids Res. 2022 Jul 22;50(13):7224-7234. doi: 10.1093/nar/gkac562.
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.
目前，嵌合寡核苷酸（ASO）治疗药物正在临床开发中，用于治疗各种疾病，包括以前难以治疗的人类疾病；然而，它们有可能引起肝毒性。尽管有几个研究小组报道了通过修饰糖残基或核苷酸键来降低嵌合 ASO 的肝毒性，但只有少数研究描述了核碱基修饰以降低肝毒性。在这项研究中，我们在致肝毒性的锁核酸嵌合寡核苷酸 ASO 中引入了单个或多个组合的 17 种核碱基衍生物，包括四个新衍生物，并研究了它们对肝毒性的影响。结果表明，成功鉴定出了可强烈降低嵌合 ASO 肝毒性的化学修饰。这种方法扩展了设计具有最佳治疗特性的嵌合 ASO 的能力。
