Identification of nucleobase chemical modifications that reduce the hepatotoxicity of gapmer antisense oligonucleotides

被引:22
作者
Yoshida, Tokuyuki [1 ]
Morihiro, Kunihiko [2 ,3 ,6 ]
Naito, Yuki [4 ,5 ]
Mikami, Atsushi [2 ]
Kasahara, Yuuya [2 ,3 ]
Inoue, Takao [1 ]
Obika, Satoshi [2 ,3 ]
机构
[1] Natl Inst Hlth Sci, Div Mol Target & Gene Therapy Prod, Kawasaki, Kanagawa, Japan
[2] Osaka Univ, Grad Sch Pharmaceut Sci, Suita, Osaka, Japan
[3] Natl Inst Biomed Innovat Hlth & Nutr NIBIOHN, Ibaraki, Osaka, Japan
[4] Database Ctr Life Sci DBCLS, 1111 Yata, Mishima, Shizuoka 4118540, Japan
[5] Natl Inst Genet, 1111 Yata, Mishima, Shizuoka 4118540, Japan
[6] Univ Tokyo, Dept Chem & Biotechnol, Grad Sch Engn, Bunkyo Ku, Tokyo, Japan
关键词
SITE-SPECIFIC INCORPORATION; SHOW IMPROVED POTENCY; PHOSPHOROTHIOATE OLIGONUCLEOTIDES; THERAPEUTIC PROFILE; RNASE H1; SEQUENCE; BINDING; PROTEIN;
D O I
10.1093/nar/gkac562
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:7224 / 7234
页数:11
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