ISIS-ANGPTL3RX, an antisense inhibitor to angiopoietin-like 3, reduces plasma lipid levels in mouse models and in healthy human volunteers

Loss-of-function variants in angiopoietin-like protein 3 [ANGPTL3] have been linked in genome-wide association studies to familial combined hypolipidemia, a syndrome characterized by marked reduction of all plasma lipoproteins, improved insulin sensitivity, absence of hepatic steatosis and reduced risk of CVD. Given these data, second generation antisense oligonucleotides (ASOs) were designed to reduce ANGPTL3 mRNA in preclinical models and humans. In normocholesterolemic mice, dose-dependent reductions in hepatic ANGPTL3 mRNA and plasma ANGPTL3 protein were observed, with modest effects on plasma lipids. However, in LDLr -/- mice, a model of homozygous familial hypercholesterolemia, potent, dose-dependent reductions of ANGPTL3 were noted with corresponding mean reductions in plasma triglycerides (TG) (up to 80%), total cholesterol (TC) (up to 66%), and reduced atherosclerosis vs. controls.