PCSK9, the short track road from discovery as drug target towards the clinic
Presented by Gilles Lambert, MD, Université de la Réunion, Sainte-Clotilde, France
According to Gilles Lambert the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a therapeutic target started with the LDL receptor (LDL-R). The LDL-R situates on the surface of most cell types, but most importantly on liver cells. It is the main receptor by which LDL is cleared from the circulation. When LDL binds, the complex undergoes endocytosis. Inside the cell, the complex separates in the endosome whereupon LDL continues to the lysosome for degradation and the receptor returns to the cell surface to again extract cholesterol from the blood.
PCSK9 is a natural inhibitor of the LDL-receptor
The LDL-R is targeted by PCSK9 to the lysosome for subsequent degradation. PCSK9 is in an enzyme produced by many cell types, but most importantly in the liver. PCSK9 cleaves its own prodomain, which enables the enzyme to migrate outside the cell. There, it naturally binds and thereby dose-dependently prevents detachment from LDL and recycling back to the cell surface. As LDL is normally degraded in the lysosome, the LDL-R is now taken along for degradation. In other words, PCSK9 is a natural inhibitor of the LDL-R.
The first mutations in patients with familial hypercholesterolaemia (FH) were detected in LDL-R as well as in ApoB. Later, also PCSK9 mutations were detected in FH patients who did not carry LDL-R or ApoB mutations1. This pointed in the direction of a role for PCSK9 in lipid metabolism and ultimately led to the discovery that gain-of-function mutations in PCSK9 were associated with increased LDL-c levels2. On the other hand, loss-of-function mutations have been detected in 2% of the African-American population and were associated with lower LDL-c levels and an 88% reduction in coronary heart disease (CHD) risk over a period of 15 years3. This observation was followed by the development of PCSK9 inhibitors.
Two approaches of PCSK9 inhibition have been successfully developed; siRNAs that block the PCSK9 synthesis, and monoclonal antibodies that prevent PCSK9-binding to the LDL-R. PCSK9 antibodies as a monotherapy or on top of statins, reduce LDL-c levels by 60% in clinical trials4,5. Interestingly, whereas statins have no additional effect on lipoprotein a, or Lp(a), levels, PCSK9 inhibitors can reduce Lp(a) by 30%. Lambert explained that PCSK9 probably does not achieve this through targeting the Lp(a) catabolism, but rather enhances Lp(a) hepatic secretion.