{"title":"Improved Efficacy and Tolerability of Antisense Oligonucleotide with Guanidine-Bridged Nucleic Acid.","authors":"Takaaki Kawanobe, Ajaya Ram Shrestha, Hideaki Tomita","doi":"10.1177/21593337261502560","DOIUrl":null,"url":null,"abstract":"<p><p>Guanidine-bridged nucleic acid (GuNA) is a bridged nucleic acid analog with high binding affinity toward complementary strands along with high nuclease resistance. GuNA has been developed to improve pharmacokinetics and safety profiles of phosphorothioate modified gapmers. Here, we evaluated antisense oligonucleotides (ASOs) modified with combination of GuNA and 2'-<i>O</i>-methoxyethyl (MOE) and found that the dual-modification strategy could significantly improve knockdown activity <i>in vitro</i> and <i>in vivo</i>. Long-term efficacy evaluation showed that intracerebroventricularly administered GuNA-modified gapmers stayed active for over 24 weeks in mouse brain. Furthermore, we observed that GuNA-modified gapmers could evade lymphocyte-derived immune responses and kept ASO-induced toxicity in check. Taken together, the results of this study demonstrate that GuNA modification can improve the functional potential of ASOs, especially in the central nervous system.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":"21593337261502560"},"PeriodicalIF":4.5000,"publicationDate":"2026-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nucleic acid therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/21593337261502560","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Guanidine-bridged nucleic acid (GuNA) is a bridged nucleic acid analog with high binding affinity toward complementary strands along with high nuclease resistance. GuNA has been developed to improve pharmacokinetics and safety profiles of phosphorothioate modified gapmers. Here, we evaluated antisense oligonucleotides (ASOs) modified with combination of GuNA and 2'-O-methoxyethyl (MOE) and found that the dual-modification strategy could significantly improve knockdown activity in vitro and in vivo. Long-term efficacy evaluation showed that intracerebroventricularly administered GuNA-modified gapmers stayed active for over 24 weeks in mouse brain. Furthermore, we observed that GuNA-modified gapmers could evade lymphocyte-derived immune responses and kept ASO-induced toxicity in check. Taken together, the results of this study demonstrate that GuNA modification can improve the functional potential of ASOs, especially in the central nervous system.
胍基桥接核酸（GuNA）是一种桥接核酸类似物，对互补链具有高结合亲和力和高核酸酶抗性。GuNA的开发是为了改善硫代酸修饰的gapmers的药代动力学和安全性。本研究对GuNA和2'- o -甲氧基乙基（MOE）联合修饰的反义寡核苷酸（ASOs）进行了评价，发现双修饰策略可以显著提高体外和体内的敲除活性。长期疗效评估显示，经脑室注射的guna修饰的gapmers在小鼠脑内保持活性超过24周。此外，我们观察到guna修饰的gapmers可以逃避淋巴细胞源性免疫反应，并抑制aso诱导的毒性。综上所述，本研究结果表明，GuNA修饰可以改善ASOs的功能潜力，特别是在中枢神经系统。
期刊介绍：
Nucleic Acid Therapeutics is the leading journal in its field focusing on cutting-edge basic research, therapeutic applications, and drug development using nucleic acids or related compounds to alter gene expression. The Journal examines many new approaches for using nucleic acids as therapeutic agents or in modifying nucleic acids for therapeutic purposes including: oligonucleotides, gene modification, aptamers, RNA nanoparticles, and ribozymes.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
