Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice.
Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice.
复制标题
将反义寡核苷酸靶向递送到肝细胞上使用三角nary n-乙酰乳糖胺可提高小鼠的效力10倍。
DOI：
10.1093/nar/gku531
复制
发表时间：
2014-07
影响因子：
14.9
通讯作者：
Seth PP
中科院分区：
文献类型：
--
作者：
Prakash TP;Graham MJ;Yu J;Carty R;Low A;Chappell A;Schmidt K;Zhao C;Aghajan M;Murray HF;Riney S;Booten SL;Murray SF;Gaus H;Crosby J;Lima WF;Guo S;Monia BP;Swayze EE;Seth PP
三触角N-乙酰半乳糖胺（GalNAc，GN 3）是肝细胞特异性脱唾液酸糖蛋白受体（ASGPR）的高亲和力配体，可使第二代缺口体反义寡核苷酸（ASO）在小鼠肝脏中的效力提高6-10倍。当与由短S-cEt（S-2′-O-Et-2′，4 ′-桥接核酸）缺口聚物ASO组成的下一代阿索设计组合时，观察到相对于亲本莫伊（2′-O-甲氧基乙基RNA）阿索，效价提高了约60倍。GN 3-缀合的ASO显示出对小鼠ASGPR的高亲和力，这导致与非实质细胞相比增强的阿索向肝细胞的递送。在内化到细胞中之后，GN 3-阿索缀合物在肝脏中代谢以释放母体阿索。在血浆中未检测到GN 3-阿索缀合物的代谢，表明GN 3充当肝细胞靶向前药，其在内化到肝脏中后通过代谢与阿索分离。GalNAc偶联还增强了两种ASO在转基因小鼠中靶向人载脂蛋白C-III和人甲状腺素运载蛋白（TTR）的效力和作用持续时间。未结合的ASO目前处于治疗家族性乳糜微粒血症和TTR介导的多发性神经病的晚期临床试验中。在人类中转化这些观察结果的能力提供了改善治疗指数、降低治疗成本和支持使用ASO治疗性抑制肝脏中基因表达的每月给药方案的潜力。
Triantennary N-acetyl galactosamine (GalNAc, GN3), a high-affinity ligand for the hepatocyte-specific asialoglycoprotein receptor (ASGPR), enhances the potency of second-generation gapmer antisense oligonucleotides (ASOs) 6–10-fold in mouse liver. When combined with next-generation ASO designs comprised of short S-cEt (S-2′-O-Et-2′,4′-bridged nucleic acid) gapmer ASOs, ∼60-fold enhancement in potency relative to the parent MOE (2′-O-methoxyethyl RNA) ASO was observed. GN3-conjugated ASOs showed high affinity for mouse ASGPR, which results in enhanced ASO delivery to hepatocytes versus non-parenchymal cells. After internalization into cells, the GN3-ASO conjugate is metabolized to liberate the parent ASO in the liver. No metabolism of the GN3-ASO conjugate was detected in plasma suggesting that GN3 acts as a hepatocyte targeting prodrug that is detached from the ASO by metabolism after internalization into the liver. GalNAc conjugation also enhanced potency and duration of the effect of two ASOs targeting human apolipoprotein C-III and human transthyretin (TTR) in transgenic mice. The unconjugated ASOs are currently in late stage clinical trials for the treatment of familial chylomicronemia and TTR-mediated polyneuropathy. The ability to translate these observations in humans offers the potential to improve therapeutic index, reduce cost of therapy and support a monthly dosing schedule for therapeutic suppression of gene expression in the liver using ASOs.
登录
查看更多内容
影响因子：
3.4
作者：
Liu, Wei;Hou, Yufang;Jiang, Ying
通讯作者：
Jiang, Ying
DOI：
10.1161/atvbaha.113.301282
发表时间：
2013-07-01
影响因子：
8.7
作者：
Crosby, Jeffrey R.;Marzec, Ulla;Monia, Brett P.
通讯作者：
Monia, Brett P.
影响因子：
5.5
作者：
Ackermann, Elizabeth J.;Guo, Shuling;Monia, Brett P.
通讯作者：
Monia, Brett P.
影响因子：
3.4
作者：
Benson, MD;Kluve-Beckerman, B;Sloop, KW
通讯作者：
Sloop, KW
影响因子：
14.9
作者：
Marcusson, EG;Bhat, B;Dean, NM
通讯作者：
Dean, NM