PCSK9: From Basic Science Discoveries to Clinical Trials

Abstract

Unknown 15 years ago, PCSK9 (proprotein convertase subtilisin/kexin type 9) is now common parlance among scientists and clinicians interested in prevention and treatment of atherosclerotic cardiovascular disease. What makes this story so special is not its recent discovery nor the fact that it uncovered previously unknown biology but rather that these important scientific insights have been translated into an effective medical therapy in record time. Indeed, the translation of this discovery to novel therapeutic serves as one of the best examples of how genetic insights can be leveraged into intelligent target drug discovery. The PCSK9 saga is unfolding quickly but is far from complete. Here, we review major scientific understandings as they relate to the role of PCSK9 in lipoprotein metabolism and atherosclerotic cardiovascular disease and the impact that therapies designed to inhibit its action are having in the clinical setting.

Keywords: dyslipidemias; hyperlipoproteinemia type II; lipid metabolism; lipoproteins; receptors, LDL.

Figure 1. Stochastic interaction between the LDLR and LDL-bound PCSK9 terminate the receptor life

Before the discovery of PCSK9 it was understood that the LDLR can recycle hundreds of time in its ~20-hours life span. Since PCSK9 is found on one in every 500-1000 LDL particle, one can envision a scenario where one in every 500 encounters, an LDLR binds to an LDL particle harboring a molecule of PCSK9. Such a stochastic interaction will then lead to the degradation of the receptor rather to its recycling, explaining, at least in part, why LDLR recycle hundreds of times. LDLR = low-density lipoprotein receptor; LDL = low-density lipoprotein; PCSK9 = proprotein convertase subtilisin/kexin type 9

Figure 2. PCSK9 compartmentalization and function in plasma

(A) PCSK9 is found in plasma in primarily two monomeric forms; an active form representing the full-length plasma protein and an inactive/less-active shorter fragment, which is a cleavage product of the full length protein by the protease furin. The active PCSK9 is found predominantly on LDL and Lp(a) particles, but not on VLDL or chylomicron remnants. In contrast, the furin-cleaved PCSK9 is not found in association with these apoB-lipoproteins. While it is not clear whether PCSK9 (active or furin cleaved) is found in association with HDL, it was suggested the HDL can inhibit PCSK9 function. (B) PCSK9 is secreted as an active form representing the full-length plasma protein. Upon secretion, PCSK9 can take on one of two fates, which ultimately determines its function. (i) PCSK9 can interact with an LDL particle, which protects PCSK9 from being cleaved by furin and leaves the protein bound to the particle in its active form, or alternatively, (ii) PCSK9 can interact with furin, which leads to the formation of a shorter fragment of PCSK9 that exhibits at least two-fold lower affinity to LDLR with limited ability/inability to degrade it. PCSK9 = proprotein convertase subtilisin/kexin type 9; LDL = low-density lipoprotein; Lp(a) = lipoprotein(a); VLDL = very low-density lipoprotein; apoB = apolipoprotein B; HDL = high-density lipoprotein; LDLR = low-density lipoprotein receptor

Figure 2. PCSK9 compartmentalization and function in plasma

(A) PCSK9 is found in plasma in primarily two monomeric forms; an active form representing the full-length plasma protein and an inactive/less-active shorter fragment, which is a cleavage product of the full length protein by the protease furin. The active PCSK9 is found predominantly on LDL and Lp(a) particles, but not on VLDL or chylomicron remnants. In contrast, the furin-cleaved PCSK9 is not found in association with these apoB-lipoproteins. While it is not clear whether PCSK9 (active or furin cleaved) is found in association with HDL, it was suggested the HDL can inhibit PCSK9 function. (B) PCSK9 is secreted as an active form representing the full-length plasma protein. Upon secretion, PCSK9 can take on one of two fates, which ultimately determines its function. (i) PCSK9 can interact with an LDL particle, which protects PCSK9 from being cleaved by furin and leaves the protein bound to the particle in its active form, or alternatively, (ii) PCSK9 can interact with furin, which leads to the formation of a shorter fragment of PCSK9 that exhibits at least two-fold lower affinity to LDLR with limited ability/inability to degrade it. PCSK9 = proprotein convertase subtilisin/kexin type 9; LDL = low-density lipoprotein; Lp(a) = lipoprotein(a); VLDL = very low-density lipoprotein; apoB = apolipoprotein B; HDL = high-density lipoprotein; LDLR = low-density lipoprotein receptor

Figure 3. Possible effects of PCSK9 inhibition on Lp(a) metabolism

(i) Therapeutic PCSK9 inhibition prevents PCSK9 interaction with the LDLR, therefore facilitating continued recycling of the receptor and efficient clearance of Lp(a) particles; (ii and iii) PCSK9 inhibition affects LRP1 and CD36 levels or function, which results in increased Lp(a) clearance through these receptors; (iv) PCSK9 directly regulates apo(a) secretion, and the inhibition of PCSK9 prevents this process. PCSK9 = proprotein convertase subtilisin/kexin type 9; Lp(a) = lipoprotein(a); LRP1 = low- density lipoprotein receptor-related protein 1; CD36 = cluster of differentiation 36; apo(a) = apolipoprotein(a)