ANGPTL3: A Breakthrough Target in Treatment for Dyslipidemia and Atherosclerosis

Dyslipidemia is a major risk factor for atherosclerosis and subsequent cardiovascular disease (CVD). Despite conventional treatment with statins, ezetimibe, or PCSK9 inhibitors, there are cases of familial hypercholesterolemia (FH) in which LDL-C levels cannot be sufficiently lowered to the target level, resulting in failure to prevent CVD. Inhibition of Angiopoietin-like protein 3 (ANGPTL3) has emerged as a new therapeutic strategy to reduce LDL-C levels independent of the LDL receptor function. Since ANGPTL3 suppresses lipoprotein lipase (LDL) and endothelial lipase (EL) activities, its inhibition facilitates the clearance of very lowdensity lipoprotein cholesterol, decreasing both LDL-C and triglyceride (TG) levels. In fact, evinacumab, an anti-ANGPTL3 monoclonal antibody, has been shown to substantially reduce LDL-C and TG levels, even in FH patients with LDL receptor gene mutations who are resistant to the conventional treatments described above. Clinical trials have also shown that siRNA therapeutics, such as zodasiran and solbinsiran, improve lipid profiles in patients with dyslipidemia. Recently, we have begun developing a peptide-based anti-ANGPTL3 vaccine and confirmed in a preclinical FH mouse model that it significantly decreases LDL-C and TG levels, reduces atherosclerotic lesions and maintains long-term efficacy without adverse effects. In this review, we discuss the promising advances in ANGPTL3-targeted therapeutics that may overcome treatment-resistant dyslipidemia and reduce CVD risk in high-risk populations.