PCSK9

About PCSK9

PCSK9 on chromosome 1p32.3 encodes proprotein convertase subtilisin kexin type 9, a secreted protein that binds LDL receptors on liver cells and directs them to lysosomes for degradation instead of recycling to the cell surface, thereby raising blood LDL cholesterol. In 2003, French researchers led by Catherine Boileau identified gain of function PCSK9 variants as a cause of autosomal dominant hypercholesterolemia. Soon afterward, studies in the Dallas Heart Study population found that loss of function variants cause lifelong low LDL cholesterol and a marked reduction in coronary heart disease, without apparent harmful effects. This human genetic evidence validated PCSK9 as a drug target and led to unusually rapid drug development. The monoclonal antibodies evolocumab and alirocumab block circulating PCSK9 and substantially lower LDL cholesterol, including in people already taking statins, and inclisiran is a small interfering RNA that silences PCSK9 production in the liver. These therapies are used in familial hypercholesterolemia, established cardiovascular disease, and statin intolerance. PCSK9 inhibition also modestly lowers lipoprotein a. The PCSK9 story is a prominent example of how studying rare human variants can identify safe and effective drug targets.