PCSK9: FROM DISCOVERY TO THERAPEUTIC APPLICATIONS & BEYOND

Nabil G. Seidah

Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (affiliated with the University of Montreal), 110 Pine Ave West, Montreal, Quebec, Canada H2W1R7

Abstract

Proprotein convertase subtilisin kexin 9 (PCSK9) was discovered in 2003 as the last and uniquely enzymatically inactive member of a family of 9 subtilisin/kexin-like serine proteases (PCSK1- PCSK9). In the same year, two gain-of-function (GOF) mutations in the PCSK9 gene (S127R and F216L) were associated with autosomal dominant hypercholesterolaemia and, a few months later, its expression was shown to be downregulated by cholesterol in mice. Although PCSK9 and low-density lipoprotein receptor (LDLR) mRNA levels were co-regulated by cholesterol and “statins”, it was established in 2004 that PCSK9 triggers LDLR degradation, thus revealing a new level of regulation of hepatic LDLR levels. Subsequent studies confirmed and extended these data. Another breakthrough was the discovery in 2005 of loss-of-function (LOF) mutations in individuals with lifelong low levels of low-density lipoprotein cholesterol (LDLc) and reduced risk of coronary heart disease, thereby making PCSK9 an attractive therapeutic target to reduce LDLc levels. PCSK9 is highly expressed in liver hepatocytes, which are the major source of circulating PCSK9 in plasma. Following the binding of circulating PCSK9 to the EGF-A domain of the LDLR, the complex is internalized and the LDLR is targeted to lysosomes for degradation, thus resulting in a reduced LDLR expression on the hepatic cell surface, a reduced uptake of LDL particles from the blood, and a consequent rise in circulating LDLc. The most deleterious GOF mutation D374Y and others are characterized by the early occurrence of cardiovascular events. In sum, since the discovery of the role of PCSK9 in the regulation of LDLc, a paradigm shift in the treatment of hypercholesterolaemia has occurred, whereby humans with PCSK9 LOF mutations exhibit exceedingly low levels of LDLc and are protected from atherosclerosis. These findings led to the development of monoclonal antibodies targeting circulating PCSK9, which reduce LDLc levels by ∼60% and substantially improve cardiovascular outcomes in a variety of high-risk hyperlipidemic patients. In addition to monoclonal antibodies, other strategies have been developed to target PCSK9, including the possibility to silence its mRNA expression, inhibit its mRNA translation, block the autocatalytic processing of proPCSK9 and alter the interaction between PCSK9 and the LDLR. Moreover, a vaccine strategy is under evaluation. Finally, in addition to liver hepatocytes, PCSK9 is expressed to a lower extent in extrahepatic tissues such as gut, kidney, pancreas, brain and thymus. Furthermore, some data suggest that PCSK9 might also play a role in vascular smooth muscle cells, and neurons. The functions of PCSK9 in liver and extrahepatic tissues during development and in the adult have not been well defined, nor are its roles in regulating liver regeneration, inflammation, steatosis, sepsis and viral infections.

The future will tell which strategies that safely target PCSK9, including longer lasting mAbs, RNA interference, and small-molecule inhibitor approaches will find their way in clinics worldwide to treat dyslipidemia, cardiometabolic pathologies, and sepsis, which would result in affordable and safe treatments and/or prevention of life threatening conditions.