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GalNAc-siRNA
发布日期:2018-06-14 15:45:34 浏览次数 :
导读
GalNAc-siRNA是糖类化合物与siRNA形成的单缀合物,将N-乙酰化的半乳糖胺(GalNAc)以三价态的方式共价缀合到不同序列的siRNA的正义链3′末端,形成多糖-siRNA单缀合物。
        
        GalNAc-siRNA是糖类化合物与siRNA形成的单缀合物,将N-乙酰化的半乳糖胺(GalNAc)以三价态的方式共价缀合到不同序列的siRNA的正义链3′末端,形成多糖-siRNA单缀合物。GalNAc是唾液酸受体(ASGPR)的靶向性配体,其与肝脏表面细胞具有较高的亲和力及迅速内化能力,从而实现该类siRNA缀合物特异性结合膜蛋白进入胞内,该类siRNA缀合物在涉及基因过表达的肝脏相关疾病治疗中具有很好的应用潜力。
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        研究中发现,当GalNAc-siRNA单缀合物单次给药剂量为1ug/g时,皮下注射就可以实现对肝脏特定靶基因的有效沉默,沉默效率远超脂质纳米颗粒包载的siRNA。相对于时下很热的基因编辑疗法,RNAi无疑是更安全的靶向基因治疗工具。经过化学修饰优化的GalNAc-siRNA的具有更好的稳定性及干扰效率,该类siRNA缀合物在涉及基因异常高表达的肝脏相关疾病治疗中具有很好的应用潜力。
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                                                                         NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-02989-4

唾液酸受体(ASGPR)在肝脏中高度特异性表达
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In Vitro Test
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In Vivo TestGalNAc-siRNA  1ug/g  注射裸鼠,4h后处理)

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合成检测

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GalNAc-siRNA HPLC 检测结果
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GalNAc-siRNA MS 检测结果
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参考文献

Reversal of siRNA-mediated gene silencing in vivo.
Nat Biotechnol. 2018 Jul;36(6):509-511. doi: 10.1038/nbt.4136. Epub 2018 May 14. 影响因子 43.113
An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promotehemostasis in hemophilia.Nat Med. 2015 May;21(5):492-7. doi: 10.1038/nm.3847. Epub 2015 Apr 13.
Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.
Nat Commun. 2018 Feb 19;9(1):723. doi: 10.1038/s41467-018-02989-4.
Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates.
Mol Ther. 2018 Mar 7;26(3):708-717. doi: 10.1016/j.ymthe.2017.12.021. Epub 2018 Jan 4.
Impact of enhanced metabolic stability on pharmacokinetics and pharmacodynamics of GalNAc-siRNA conjugates.
Nucleic Acids Res. 2017 Nov 2;45(19):10969-10977. doi: 10.1093/nar/gkx818.


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