ANGPTL3 gene mRNA (hepatic)

Class

GalNAc-conjugated small interfering RNA (siRNA) — ANGPTL3-targeted RNAi therapeutic

Pathway

Silences hepatic ANGPTL3 mRNA translation, lowering LDL-C and triglycerides via reduced inhibition of lipoprotein/endothelial lipase

ANGPTL3 (angiopoietin-like 3) is a liver-derived protein that normally restrains two enzymes, lipoprotein lipase and endothelial lipase, which break down triglyceride-rich lipoproteins in the bloodstream. By inhibiting these enzymes, ANGPTL3 keeps circulating levels of triglycerides and, indirectly, LDL cholesterol higher than they would otherwise be. People who carry natural loss-of-function mutations in the ANGPTL3 gene have markedly lower LDL cholesterol and triglycerides throughout life, with no clear signs of harm, which has made the gene an attractive target for treating stubborn lipid disorders. Zodasiran works through RNA interference (RNAi): a small interfering RNA (siRNA) molecule is chemically linked to a sugar tag (GalNAc) that directs it specifically to liver cells, where it is taken up and used to degrade ANGPTL3 messenger RNA before it can be translated into protein. Lowering hepatic ANGPTL3 protein relieves its inhibitory grip on lipoprotein and endothelial lipase, allowing more efficient clearance of triglyceride-rich particles and a reduction in LDL cholesterol. This mechanism is relevant to severe or genetic forms of dyslipidemia, including cases resistant to standard cholesterol-lowering approaches, and to hypertriglyceridemia more broadly.