From Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
N Engl J Med. 2017 Jul 20;377(3):222-232. doi: 10.1056/NEJMoa1701329. Epub 2017 May 24.
Epidemiologic and genomewide association studies have linked loss-of-function variants in ANGPTL3, encoding angiopoietin-like 3, with low levels of plasma lipoproteins.
We evaluated antisense oligonucleotides (ASOs) targeting Angptl3 messenger RNA (mRNA) for effects on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis in mice. Subsequently, 44 human participants (with triglyceride levels of either 90 to 150 mg per deciliter [1.0 to 1.7 mmol per liter] or >150 mg per deciliter, depending on the dose group) were randomly assigned to receive subcutaneous injections of placebo or an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg per week for 6 weeks). The main end points were safety, side-effect profile, pharmacokinetic and pharmacodynamic measures, and changes in levels of lipids and lipoproteins.
The treated mice had dose-dependent reductions in levels of hepatic Angptl3 mRNA, Angptl3 protein, triglycerides, and low-density lipoprotein (LDL) cholesterol, as well as reductions in liver triglyceride content and atherosclerosis progression and increases in insulin sensitivity. After 6 weeks of treatment, persons in the multiple-dose groups had reductions in levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from baseline, P<0.01 for all doses vs. placebo) and in levels of triglycerides (reductions of 33.2 to 63.1%), LDL cholesterol (1.3 to 32.9%), very-low-density lipoprotein cholesterol (27.9 to 60.0%), non-high-density lipoprotein cholesterol (10.0 to 36.6%), apolipoprotein B (3.4 to 25.7%), and apolipoprotein C-III (18.9 to 58.8%). Three participants who received the antisense oligonucleotide and three who received placebo reported dizziness or headache. There were no serious adverse events.
Oligonucleotides targeting mouse Angptl3 retarded the progression of atherosclerosis and reduced levels of atherogenic lipoproteins in mice. Use of the same strategy to target human ANGPTL3 reduced levels of atherogenic lipoproteins in humans. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov number, NCT02709850 .).
血管生成素样蛋白 3（ANGPTL3）编码的基因失活变体与血浆脂蛋白水平降低有关，这已在流行病学和全基因组关联研究中得到证实。
我们评估了针对 Angptl3 信使 RNA（mRNA）的反义寡核苷酸（ASO）对小鼠血浆脂质水平、甘油三酯清除率、肝甘油三酯含量、胰岛素敏感性和动脉粥样硬化的影响。随后，44 名参与者（根据剂量组，甘油三酯水平在 90 至 150 毫克/分升[1.0 至 1.7 毫摩尔/升]或 >150 毫克/分升）被随机分配接受皮下注射安慰剂或靶向 ANGPTL3 mRNA 的反义寡核苷酸，剂量为单次 20、40 或 80 毫克，或多次 10、20、40 或 60 毫克/周，共 6 周。主要终点是安全性、副作用谱、药代动力学和药效学指标以及血脂和脂蛋白水平的变化。
经治疗的小鼠肝 Angptl3 mRNA、Angptl3 蛋白、甘油三酯和低密度脂蛋白（LDL）胆固醇水平呈剂量依赖性降低，肝甘油三酯含量和动脉粥样硬化进展减少，胰岛素敏感性增加。经过 6 周的治疗，多剂量组的人 ANGPTL3 蛋白水平降低（与安慰剂相比，所有剂量组降低 46.6%至 84.5%，均<0.01），甘油三酯水平降低（降低 33.2%至 63.1%）、LDL 胆固醇（降低 1.3%至 32.9%）、极低密度脂蛋白胆固醇（降低 27.9%至 60.0%）、非高密度脂蛋白胆固醇（降低 10.0%至 36.6%）、载脂蛋白 B（降低 3.4%至 25.7%）和载脂蛋白 C-III（降低 18.9%至 58.8%）。接受反义寡核苷酸治疗的 3 名参与者和接受安慰剂治疗的 3 名参与者报告有头晕或头痛。没有严重的不良事件。
靶向小鼠 Angptl3 的寡核苷酸可延缓动脉粥样硬化的进展，并降低小鼠致动脉粥样硬化脂蛋白的水平。使用相同的策略靶向人类 ANGPTL3 可降低人类致动脉粥样硬化脂蛋白的水平。（由 Ionis 制药公司资助；ClinicalTrials.gov 编号，NCT02709850）。
