Progetto vincitore della Borsa di Studio SISA 2017 - De Stefano

Binding of PCSK9 to circulating LDL: effect of PCSK9 monoclonal antibodies on the LDL-bound PCSK9?

Daniela De Stefano

Abstract:

Cardiovascular disease (CVD) is the leading cause of death in all countries. Hypercholesterolemia is directly correlated to atherosclerosis development, leading to coronary heart disease (CHD) and stroke. Familial hypercholesterolemia (FH) is known to cause premature atherosclerosis in humans. Current lipid-lowering therapies, statins and ezetimibe, have been reported to fail to reach the goal in up to 50% of patients.

Moreover, intolerance to statin is recognized as a major hurdle to full implementation to statin therapy and together with their perceived effect on the incidence of new onset diabetes reduces patient compliance.
These unmet needs have warranted the search for new, potent, and safe cholesterol-lowering therapies. Proprotein convertase subtilisin/kexin 9 (PCSK9), a circulating serine protease, binds LDLR leading to its intracellular degradation6. Gain-of-function mutations in PCSK9 are a cause of FH while loss-of-function mutations are associated with low LDL-C and low lifelong CVD risk.

Inhibiting the interaction of PCSK9 with LDLR using monoclonal antibodies (mAbs) significantly lowers LDL-Clevels (more than 50%) and reduces cardiovascular risk. The PCSK9 mAbs also significantly and dose-dependently reduce lipoprotein (a) by up to
30% whereas the effect of PCSK9 inhibition on serum triglyceride (TGs) levels has not been consistently demonstrated. The existence of PCSK9-LDL complexes in human plasma has been proved. The aim of this project is to elucidate whether therapeutic mAbs interfere with PCSK9 binding to LDL and, if so, the consequences of this effect.