Background and Aims Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase to regulate tissue fatty acid uptake from triglyceride-rich lipoproteins such as VLDL. While pharmacological inhibition of ANGPTL3 is being evaluated as lipid-lowering strategy, systemic ANGPTL4 inhibition is not pursued due to adverse effects. This study aimed to compare the therapeutic potential of liver-specific Angptl3 and Angptl4 silencing to attenuate hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established humanized model for lipoprotein metabolism. Methods and results Mice were subcutaneously injected twice-weekly with saline or liver-targeted antisense oligonucleotides against Angptl3, Angptl4, both, or a scrambled oligonucleotide. Plasma lipid levels, VLDL clearance and hepatic VLDL production were determined, and atherosclerosis development was assessed. For toxicological evaluation, cynomolgus monkeys were treated with three dosages of liver-targeted ANGPTL4-silencing oligonucleotides. Liver-targeted Angptl4 silencing reduced plasma triglycerides (-48%) and total cholesterol (-56%), explained by higher VLDL-derived fatty acid uptake by brown adipose tissue and lower VLDL production by the liver. Accordingly, Angptl4 silencing reduced atherosclerotic lesion size (-86%) and improved lesion stability. Hepatic Angptl3 silencing similarly attenuated hyperlipidemia and atherosclerosis development. While Angptl3 and Angptl4 silencing lowered plasma triglycerides in the refed and fasted state, respectively, combined Angptl3/4 silencing lowered plasma triglycerides independent of nutritional state. In cynomolgus monkeys, anti-ANGPTL4 ASO treatment was well tolerated without adverse effects. Conclusions Liver-targeted Angptl4 silencing potently attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, and liver-targeted ANGPTL4 silencing is well-tolerated in non-human primates. These data warrant further clinical development of liver-targeted ANGPTL4 silencing.

中文翻译：

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通过反义寡核苷酸治疗进行肝脏靶向 Angptl4 沉默可减轻 APOE*3-Leiden.CETP 小鼠的高脂血症和动脉粥样硬化的发展


背景和目的 血管生成素样 3 (ANGPTL3) 和 4 (ANGPTL4) 抑制脂蛋白脂肪酶，调节组织从富含甘油三酯的脂蛋白（如 VLDL）中摄取脂肪酸。虽然 ANGPTL3 的药理抑制正在被评估为降脂策略，但由于不良反应，并未采用全身性 ANGPTL4 抑制。本研究旨在比较肝脏特异性 Angptl3 和 Angptl4 沉默对减轻 APOE*3-Leiden.CETP 小鼠高脂血症和动脉粥样硬化发展的治疗潜力，APOE*3-Leiden.CETP 小鼠是一种完善的脂蛋白代谢人源化模型。方法和结果小鼠每周两次皮下注射盐水或针对Angptl3、Angptl4或两者的肝脏靶向反义寡核苷酸或乱序寡核苷酸。测定血浆脂质水平、VLDL清除率和肝脏VLDL产生，并评估动脉粥样硬化的发展。为了进行毒理学评估，用三种剂量的肝脏靶向 ANGPTL4 沉默寡核苷酸治疗食蟹猴。肝脏靶向的 Angptl4 沉默降低了血浆甘油三酯 (-48%) 和总胆固醇 (-56%)，这是由于棕色脂肪组织对 VLDL 衍生脂肪酸的吸收增加以及肝脏产生的 VLDL 减少所致。因此，Angptl4 沉默减少了动脉粥样硬化病变的大小 (-86%) 并改善了病变的稳定性。肝脏 Angptl3 沉默同样可以减弱高脂血症和动脉粥样硬化的发展。虽然 Angptl3 和 Angptl4 沉默分别降低了进食和禁食状态下的血浆甘油三酯，但联合 Angptl3/4 沉默降低了血浆甘油三酯，而与营养状态无关。在食蟹猴中，抗 ANGPTL4 ASO 治疗耐受性良好，没有不良反应。 结论 肝脏靶向 ANGPTL4 沉默可有效减轻 APOE*3-Leiden.CETP 小鼠的高脂血症和动脉粥样硬化发展，并且肝脏靶向 ANGPTL4 沉默在非人灵长类动物中具有良好的耐受性。这些数据保证了肝脏靶向 ANGPTL4 沉默的进一步临床开发。