ANGPTL3 and Apolipoprotein C-III as Novel Lipid-Lowering Targets

AbstractPurpose of ReviewDespite significant progress in plasma lipid lowering strategies, recent clinical trials highlight the existence of residual cardiovascular risk. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (Apo C-III) have been identified as novel lipid-lowering targets.Recent FindingsApo C-III and ANGPTL3 have emerged as novel regulators of triglyceride (TG) and low-density lipoprotein-cholesterol (LDL-C) levels. ANGPTL3 is an inhibitor of lipoprotein lipase (LPL), reducing lipolysis of Apo B-containing lipoproteins. Loss-of-functionANGPLT3 mutations are associated with reduced plasma cholesterol and TG, while novel ANGPLT3 inhibition strategies, including monoclonal antibodies (evinacumab),ANGPLT3 antisense oligonucleotides (IONIS-ANGPTL3-LRx), and small interfering RNA (siRNA) silencing techniques (ARO-ANG3), result in increased lipolysis and significant reductions of LDL-C and TG levels in phase I and II clinical trials. Similarly, Apo C-III inhibits LPL while promoting the hepatic secretion of TG-rich lipoproteins and preventing their clearance. Loss-of-functionAPOC3 mutations have been associated with reduced TG levels. Targeting of Apo C-III with volanesorsen, anAPOC3 siRNA, results in significant reduction in plasma TG levels but possibly also increased risk for thrombocytopenia, as recently demonstrated in phase I, II, and III clinical trials. ARO-APOC3 is a novel siRNA-based agent targeting Apo C-III which is currently under investigation...

Source: Current Atherosclerosis Reports - March 10, 2021 Category: Cardiology Source Type: research