Editing out cardiovascular risk: A narrative review of gene-editing approaches to PCSK9

Background

PCSK9 is a circulating protease that regulates plasma low-density lipoprotein (LDL) cholesterol levels. It binds to the LDL receptor on the surface of hepatocytes and directs the receptor toward intracellular degradation, so that greater PCSK9 activity leaves fewer LDL receptors available to clear LDL-C from the bloodstream. PCSK9 was established as a drug target largely through human genetics: naturally occurring loss-of-function variants are associated with lifelong low LDL-C and a markedly reduced risk of atherosclerotic cardiovascular disease with no apparent adverse consequences, whereas gain-of-function variants cause a severe, early onset form of familial hypercholesterolemia. Pharmacological PCSK9 inhibitors, monoclonal antibodies, and small interfering RNA (siRNAs) are currently in clinical use; however, all require repeated, lifelong administration.