• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

筛选具有有限脱靶驱动大鼠肝毒性的GalNAc缀合小干扰RNA。

Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.

作者信息

Janas Maja M, Schlegel Mark K, Harbison Carole E, Yilmaz Vedat O, Jiang Yongfeng, Parmar Rubina, Zlatev Ivan, Castoreno Adam, Xu Huilei, Shulga-Morskaya Svetlana, Rajeev Kallanthottathil G, Manoharan Muthiah, Keirstead Natalie D, Maier Martin A, Jadhav Vasant

机构信息

Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.

出版信息

Nat Commun. 2018 Feb 19;9(1):723. doi: 10.1038/s41467-018-02989-4.

DOI:10.1038/s41467-018-02989-4
PMID:29459660
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5818625/
Abstract

Small interfering RNAs (siRNAs) conjugated to a trivalent N-acetylgalactosamine (GalNAc) ligand are being evaluated in investigational clinical studies for a variety of indications. The typical development candidate selection process includes evaluation of the most active compounds for toxicity in rats at pharmacologically exaggerated doses. The subset of GalNAc-siRNAs that show rat hepatotoxicity is not advanced to clinical development. Potential mechanisms of hepatotoxicity can be associated with the intracellular accumulation of oligonucleotides and their metabolites, RNA interference (RNAi)-mediated hybridization-based off-target effects, and/or perturbation of endogenous RNAi pathways. Here we show that rodent hepatotoxicity observed at supratherapeutic exposures can be largely attributed to RNAi-mediated off-target effects, but not chemical modifications or the perturbation of RNAi pathways. Furthermore, these off-target effects can be mitigated by modulating seed-pairing using a thermally destabilizing chemical modification, which significantly improves the safety profile of a GalNAc-siRNA in rat and may minimize the occurrence of hepatotoxic siRNAs across species.

摘要

与三价N-乙酰半乳糖胺（GalNAc）配体缀合的小干扰RNA（siRNA）正在针对多种适应症进行临床研究评估。典型的研发候选药物筛选过程包括在药理学上的超剂量下评估大鼠中最具活性化合物的毒性。显示大鼠肝毒性的GalNAc-siRNA子集不会进入临床开发阶段。肝毒性的潜在机制可能与寡核苷酸及其代谢产物的细胞内积累、基于RNA干扰（RNAi）介导的杂交脱靶效应和/或内源性RNAi途径的扰动有关。在这里，我们表明在超治疗剂量下观察到的啮齿动物肝毒性在很大程度上可归因于RNAi介导的脱靶效应，而不是化学修饰或RNAi途径的扰动。此外，通过使用热不稳定化学修饰调节种子配对可以减轻这些脱靶效应，这显著改善了GalNAc-siRNA在大鼠中的安全性，并可能使跨物种肝毒性siRNA的发生率降至最低。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7dc/5818625/b7874939e6dd/41467_2018_2989_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7dc/5818625/912dc5c67014/41467_2018_2989_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7dc/5818625/02cf0f80f909/41467_2018_2989_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7dc/5818625/4515adbf4c13/41467_2018_2989_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7dc/5818625/270a1bddb903/41467_2018_2989_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7dc/5818625/ee088b4f7366/41467_2018_2989_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7dc/5818625/b7874939e6dd/41467_2018_2989_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7dc/5818625/912dc5c67014/41467_2018_2989_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7dc/5818625/02cf0f80f909/41467_2018_2989_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7dc/5818625/4515adbf4c13/41467_2018_2989_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7dc/5818625/270a1bddb903/41467_2018_2989_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7dc/5818625/ee088b4f7366/41467_2018_2989_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7dc/5818625/b7874939e6dd/41467_2018_2989_Fig6_HTML.jpg

相似文献

1
Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.筛选具有有限脱靶驱动大鼠肝毒性的GalNAc缀合小干扰RNA。
Nat Commun. 2018 Feb 19;9(1):723. doi: 10.1038/s41467-018-02989-4.
2
The Nonclinical Safety Profile of GalNAc-conjugated RNAi Therapeutics in Subacute Studies.GalNAc缀合的RNAi疗法在亚急性研究中的非临床安全性概况。
Toxicol Pathol. 2018 Oct;46(7):735-745. doi: 10.1177/0192623318792537. Epub 2018 Aug 23.
3
Evaluating the oral delivery of GalNAc-conjugated siRNAs in rodents and non-human primates.评估 GalNAc 缀合 siRNA 在啮齿动物和非人类灵长类动物中的口服递送。
Nucleic Acids Res. 2024 Jun 10;52(10):5423-5437. doi: 10.1093/nar/gkae350.
4
Hepatocyte-specific delivery of siRNAs conjugated to novel non-nucleosidic trivalent N-acetylgalactosamine elicits robust gene silencing in vivo.与新型非核苷三价N-乙酰半乳糖胺偶联的小干扰RNA（siRNA）的肝细胞特异性递送在体内引发了强大的基因沉默。
Chembiochem. 2015 Apr 13;16(6):903-8. doi: 10.1002/cbic.201500023. Epub 2015 Mar 18.
5
Plasma Pharmacokinetics of N-Acetylgalactosamine-Conjugated Small-Interfering Ribonucleic Acids (GalNAc-Conjugated siRNAs).N-乙酰半乳糖胺偶联小干扰核糖核酸（GalNAc 偶联 siRNAs）的血浆药代动力学。
Clin Pharmacokinet. 2023 Dec;62(12):1661-1672. doi: 10.1007/s40262-023-01314-7. Epub 2023 Oct 12.
6
Overcoming GNA/RNA base-pairing limitations using isonucleotides improves the pharmacodynamic activity of ESC+ GalNAc-siRNAs.使用异核苷酸克服 GNA/RNA 碱基配对限制可提高 ESC+GalNAc-siRNAs 的药效活性。
Nucleic Acids Res. 2021 Nov 8;49(19):10851-10867. doi: 10.1093/nar/gkab916.
7
Impact of Serum Proteins on the Uptake and RNAi Activity of GalNAc-Conjugated siRNAs.血清蛋白对 GalNAc 缀合 siRNA 的摄取和 RNAi 活性的影响。
Nucleic Acid Ther. 2021 Aug;31(4):309-315. doi: 10.1089/nat.2020.0919. Epub 2021 Apr 15.
8
siRNA Design and GalNAc-Empowered Hepatic Targeted Delivery.siRNA 设计与 GalNAc 赋能的肝靶向递送。
Methods Mol Biol. 2021;2282:77-100. doi: 10.1007/978-1-0716-1298-9_6.
9
In Vitro Drug-Drug Interaction Evaluation of GalNAc Conjugated siRNAs Against CYP450 Enzymes and Transporters.GalNAc 缀合 siRNAs 对 CYP450 酶和转运体的体外药物相互作用评价。
Drug Metab Dispos. 2019 Oct;47(10):1183-1194. doi: 10.1124/dmd.119.087098. Epub 2019 Jul 3.
10
A combinatorial approach for achieving CNS-selective RNAi.实现中枢神经系统选择性 RNAi 的组合方法。
Nucleic Acids Res. 2024 May 22;52(9):5273-5284. doi: 10.1093/nar/gkae100.

引用本文的文献

1
Chemical Modifications in Nucleic Acid Therapeutics.核酸疗法中的化学修饰
Methods Mol Biol. 2025;2965:57-126. doi: 10.1007/978-1-0716-4742-4_3.
2
Dual-targeted siRubicon delivery strategy triggers hepatocellular lipophagy for mitigating liver steatosis.双靶点siRubicon递送策略触发肝细胞脂肪自噬以减轻肝脏脂肪变性。
Nat Commun. 2025 Aug 12;16(1):7455. doi: 10.1038/s41467-025-61965-x.
3
Single alkyl phosphonate modification of the siRNA backbone in the seed region enhances specificity and therapeutic profile.种子区域中siRNA骨架的单烷基膦酸酯修饰可提高特异性和治疗效果。

本文引用的文献

1
Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates.GalNAc-siRNA 缀合物的高级 siRNA 设计可进一步改善体内性能。
Mol Ther. 2018 Mar 7;26(3):708-717. doi: 10.1016/j.ymthe.2017.12.021. Epub 2018 Jan 4.
2
Chirality Dependent Potency Enhancement and Structural Impact of Glycol Nucleic Acid Modification on siRNA.手性依赖性效力增强和糖核酸修饰对 siRNA 的结构影响。
J Am Chem Soc. 2017 Jun 28;139(25):8537-8546. doi: 10.1021/jacs.7b02694. Epub 2017 Jun 19.
3
Cellular uptake and trafficking of antisense oligonucleotides.
Nucleic Acids Res. 2025 Jul 19;53(14). doi: 10.1093/nar/gkaf692.
4
Therapeutic Approaches of Viral Gene Silencing by Small Interfering RNA: Strategies to Prevent the Emergence of Antiviral Resistant Escape Mutants.小干扰RNA介导的病毒基因沉默治疗方法：预防抗病毒耐药逃逸突变体出现的策略
Pharmaceuticals (Basel). 2025 Jul 1;18(7):987. doi: 10.3390/ph18070987.
5
RNA chemistry and therapeutics.RNA化学与治疗学。
Nat Rev Drug Discov. 2025 Jul 14. doi: 10.1038/s41573-025-01237-x.
6
mRNA vaccines and SiRNAs targeting cancer immunotherapy: challenges and opportunities.靶向癌症免疫治疗的mRNA疫苗和小干扰RNA：挑战与机遇
Discov Oncol. 2025 Jul 5;16(1):1265. doi: 10.1007/s12672-025-03070-5.
7
Cross-species translational modelling of targeted therapeutic oligonucleotides using physiologically based pharmacokinetics.使用基于生理学的药代动力学对靶向治疗性寡核苷酸进行跨物种翻译建模。
J Pharmacokinet Pharmacodyn. 2025 Jun 12;52(4):35. doi: 10.1007/s10928-025-09980-9.
8
Targeting CIDEB alleviates liver steatosis and fibrosis in mouse MASH models.靶向CIDEB可减轻小鼠MASH模型中的肝脂肪变性和纤维化。
Mol Ther Nucleic Acids. 2025 May 19;36(2):102567. doi: 10.1016/j.omtn.2025.102567. eCollection 2025 Jun 10.
9
Characterization of Hepatotropic Small Molecule Inhibitors of Hypoxia Inducible Factor Prolyl Hydroxylase in the Prevention of Oxygen-Induced Retinopathy.缺氧诱导因子脯氨酰羟化酶的肝靶向小分子抑制剂在预防氧诱导视网膜病变中的特性研究
J Med Chem. 2025 Jun 26;68(12):12392-12401. doi: 10.1021/acs.jmedchem.4c02186. Epub 2025 Jun 4.
10
Design, pharmacology, and toxicology of a novel chemically modified siRNA targeting hepatic angiotensinogen.一种靶向肝脏血管紧张素原的新型化学修饰小干扰RNA的设计、药理学及毒理学
Mol Ther Nucleic Acids. 2025 Apr 17;36(2):102542. doi: 10.1016/j.omtn.2025.102542. eCollection 2025 Jun 10.
反义寡核苷酸的细胞摄取和转运。
Nat Biotechnol. 2017 Mar;35(3):230-237. doi: 10.1038/nbt.3779. Epub 2017 Feb 27.
4
Impact of Oligonucleotide Structure, Chemistry, and Delivery Method on In Vitro Cytotoxicity.寡核苷酸结构、化学性质及递送方法对体外细胞毒性的影响
Nucleic Acid Ther. 2017 Feb;27(1):11-22. doi: 10.1089/nat.2016.0639. Epub 2016 Dec 6.
5
siRNA carrying an (E)-vinylphosphonate moiety at the 5΄ end of the guide strand augments gene silencing by enhanced binding to human Argonaute-2.在引导链5΄端携带（E）-乙烯基膦酸酯部分的小干扰RNA通过增强与人源AGO2的结合来增强基因沉默。
Nucleic Acids Res. 2017 Apr 7;45(6):3528-3536. doi: 10.1093/nar/gkw1171.
6
Exposure to siRNA-GalNAc Conjugates in Systems of the Standard Test Battery for Genotoxicity.在遗传毒性标准测试组合系统中接触小干扰RNA- N-乙酰半乳糖胺缀合物。
Nucleic Acid Ther. 2016 Dec;26(6):363-371. doi: 10.1089/nat.2016.0622. Epub 2016 Jul 7.
7
Anatomy of RISC: how do small RNAs and chaperones activate Argonaute proteins?RNA诱导沉默复合体的剖析：小RNA和伴侣蛋白如何激活AGO蛋白？
Wiley Interdiscip Rev RNA. 2016 Sep;7(5):637-60. doi: 10.1002/wrna.1356. Epub 2016 May 16.
8
5'-(E)-Vinylphosphonate: A Stable Phosphate Mimic Can Improve the RNAi Activity of siRNA-GalNAc Conjugates.5'-(E)-乙烯基膦酸酯：一种稳定的磷酸类似物，可以提高 siRNA-GalNAc 缀合物的 RNAi 活性。
Chembiochem. 2016 Jun 2;17(11):985-9. doi: 10.1002/cbic.201600130. Epub 2016 Apr 28.
9
RNA interference-induced hepatotoxicity results from loss of the first synthesized isoform of microRNA-122 in mice.RNA干扰诱导的肝毒性是由于小鼠中首个合成的微小RNA - 122亚型缺失所致。
Nat Med. 2016 May;22(5):557-62. doi: 10.1038/nm.4079. Epub 2016 Apr 11.
10
Rationally designed siRNAs without miRNA-like off-target repression.经过合理设计的小干扰RNA，不存在类似微小RNA的脱靶抑制效应。
BMB Rep. 2016 Mar;49(3):135-6. doi: 10.5483/bmbrep.2016.49.3.019.