Angiopoietin-like protein 3 (ANGPTL3) is an important regulator of lipoproteins by inhibiting both lipoprotein and endothelial lipases. It has been intensively investigated as a drug target for the treatment of dyslipidemia. In the present study, a modified small interfering RNA (siRNA) conjugated with GalNAc ANGsiR10 was characterized by in vivo and in vitro studies for its effect on ANGPTL3 silencing, the reduction of plasma triglycerides (TGs), and cholesterol levels in disease models. The results showed that ANGsiR10 displayed a significant and long-lasting efficacy in reducing blood TG and cholesterol levels in both mice and monkeys. Remarkably, the maximal reductions of plasma TG levels in the hApoC3-Tg mice, a model with high TG levels, and the spontaneous dyslipidemia model of rhesus monkey were 96.3% and 67.7%, respectively, after a single dose of ANGsiR10, with long-lasting effects up to 15 weeks. The cholesterol levels were also reduced in response to treatment, especially the non-HDL-c level, without altering the ApoA/ApoB ratio. This study showed that ANGsiR10 is effective in treating dyslipidemia and is worth further development.

血管生成素样蛋白 3 (ANGPTL3) 通过抑制脂蛋白和内皮脂肪酶，是脂蛋白的重要调节因子。它已作为治疗血脂异常的药物靶标进行了深入研究。在本研究中，修饰的小干扰 RNA (siRNA) 与 GalNAc ANGsiR10结合，通过体内和体外研究表征其对ANGPTL3沉默、血浆甘油三酯 (TG) 降低和疾病模型中胆固醇水平的影响。结果表明，ANGsiR10在降低小鼠和猴子的血液 TG 和胆固醇水平方面显示出显着且持久的功效。值得注意的是，hApoC3-Tg 小鼠（具有高 TG 水平的模型）和恒河猴自发性血脂异常模型中血浆 TG 水平的最大降低分别为 96.3% 和 67.7%，在单次剂量的ANGsiR10后，长期持续效果长达 15 周。胆固醇水平也因治疗而降低，尤其是非 HDL-c 水平，而不改变 ApoA/ApoB 比率。本研究表明ANGsiR10治疗血脂异常有效，值得进一步开发。