Grant: Catalyst Grant: Sex as a Variable in Biomedical Research

We discovered a family of 9 enzymes, the proprotein convertases (PCs), which are involved in producing the final forms of active proteins, and are world leaders in understanding their roles in pathologies, especially that of PCSK9 in cardiovascular diseases. PCSK9 reduces the levels of the LDLR, the clearance receptor of the bad LDL-cholesterol (LDLc), and hence too much of this enzyme results in high levels of LDLc in the blood, which are associated with coronary heart disease. PCSK9 is one of the most promising targets in medicine today, in large part thanks to our pioneering work on this protein. Until recently, it was thought that the activity of PCSK9 on LDLR is sex-independent. Using mice lacking PCSK9 (KO mice), we were the first to report that PCSK9 deficiency unmasks a sex/tissue-specific cellular localization of the LDLR, leading to reduced cell surface levels (and hence bioavailability to LDLc) in the liver of female compared to male PCSK9 KO mice. This results in a lower efficacy of LDLc clearance from the blood in female mice lacking PCSK9. New injectable treatments using a monoclonal antibody (mAb) against PCSK9 have just been accepted by the health authorities to effectively lower LDLc by 60% in hypercholesterolemic patients. Our work and a Sanofi report on the efficacy of the mAb treatment in human, pointed out a sex- and tissue-specific difference in the response to PCSK9 inhibitors, with female mice/pre-menopausal women being less responsive than males/men. Our 2-year research program will concentrate on identifying the mechanism behind the estrogen regulation of the functional activity of LDLR in the liver, under conditions where PCSK9 is either absent or low, as is the case in PCSK9 KO mice or in humans treated with a monoclonal antibody (mAb) to PCSK9. The outcome of this research will have a direct translational implication in cardiovascular clinics, especially for pre-menopausal women undergoing cholesterol-lowering therapy against PCSK9.