Inhibiting angiopoietin-like protein 3: clear skies or clouds on the horizon?

Angiopoietin-like protein 3 (ANGPTL3) is encoded by the ANGPTL3 gene which lies within an intron of the much larger DOCK7 gene on the short arm of chromosome (Chr) 1. Expression in highest in the liver, where the 7 exons of the gene are transcribed into messenger ribonucleic acid (mRNA) transcripts, yielding a mature protein of 460 amino acids that circulates in plasma. Several pharmaceutical agents inhibit ANGPTL3 production or block its activity at various stages, including genome editing with VERVE-201, RNA interference by the allele specific oligonucleotide (ASO) vupanorsen and small interfering RNA (siRNA) zodasiran, and binding to protein epitopes in plasma by the monoclonal antibody evinacumab. These drugs have been variably given to a non-human primate (NHP) model of familial hypercholesterolemia (FH), and to patients with combined hyperlipidemia (HLP), homozygous familial hypercholesterolemia (HoFH), familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS). Impact of these treatments on plasma concentrations of ANGPTL3, low-density lipoprotein cholesterol (LDL-C) and triglycerides are shown. ND means not determined in the clinical trial