Lipid metabolism and the targeting of angiopoietin-like 3: Experimental drugs under development

Angiopoietin-like protein 3 (ANGPTL3) is an important regulator of lipid metabolism [1]. ANGPTL3 inhibits lipoprotein lipase (LPL), resulting in an increase in serum triglyceride levels [2]. In addition, ANGPTL3 inhibits endothelial lipase, which in turn induces a reduction in high-density lipoprotein cholesterol (HDL-C) levels [3]. Near-complete suppression of ANGPTL3 activity is also associated with a reduction in low-density lipoprotein cholesterol (LDL-C) levels through a yet unclear mechanism [4,5]. In mendelian randomization studies, subjects with heterozygous loss-of-function variants in ANGPTL3 had lower levels of triglycerides, HDL-C and LDL-C than participants without these variants and also had 34–41% lower risk for coronary heart disease [4,5]. Several strategies that inhibit ANGPTL3 are currently under evaluation including monoclonal antibodies, antisense oligonucleotides, small interfering RNAs, vaccines and in vivo gene editing approaches to permanently knock out ANGPTL3 using clustered regularly interspaced palindromic repeats-associated protein 9 (CRISPR/Cas9). Monoclonal antibodies selectively inhibit circulating ANGPTL3. Antisense oligonucleotides are single-stranded deoxyribonucleotides, complementary to the ANGPTL3 mRNA and bind to the ANGPTL3 mRNA within the nucleus to form a DNA-RNA heteroduplex, which is then cleaved by the RNAse H endonuclease resulting in reduced mRNA translation [6]. Small interfering RNAs are doublestranded RNAs that enter into the cytoplasm to form the RNA-induced silencing complex (RISC) and then induce cleavage of the ANGPTL3 mRNA, reducing mRNA translation [6]. Vaccines aim to trigger the generation of host antibodies against ANGPTL3. The CRISPR/Cas9 system introduces double-strand breaks at desired sites within the ANGPTL3 gene, which are then repaired resulting in either frameshift mutations or in-frame insertions/deletions and therefore ANGPTL3 gene knock out [7]. Notably, statins reduce ANGPTL3 levels and therefore a blunting of the effect of agents that inhibit ANGPTL3 is expected in statin-treated patients [8]. The effects of other lipid-lowering agents, including ezetimibe and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, on ANGPTL3 levels is unknown. 2. Evinacumab