The intracellular concentration of cholesterol is a vital constant influenced by the uptake, metabolism and
excretion of cholesterol. The synthesis and expression of the PCSK9-LDLR duo is one of the most important mechanisms
to regulate this constant; in a physiological state, the yin-yang balance between PCSK9 and LDLR regulates the entry of
cholesterol into the cell to keep the intracellular cholesterol concentration stable.
The mapping of the human gene encoding the serine protease PCSK9, located at 1p32-3, has allowed the identification of
mutations with "gain" and "loss" of protease functions. Gain of function mutations causes decreased LDLR resulting in
increased LDL-C and increased incidence of cardiovascular events. Loss of function mutations have opposite effect,
increased LDLR, decreased LDL-C and decreased incidence of cardiovascular events.
The identification of human mutations with PCSK9 “loss” of function demostrated the benefit of decreased PCSK9 and
opened the door to developing new anti-PCSK9 therapies. The goal of this research area is to reduce the incidence of
cardiovascular events beyond statins; the strategy is to mimic the state of PCSK9 “loss” of function by tactics as
oligonucleotide therapies targeting PCSK9 mRNA and/or biological therapies with human monoclonal antibodies
This chapter reviews, the characteristics of the PCSK9, the physiological significance of the PCSK9-LDLR duo, and the
therapeutic implications of the human genetic models of PCSK9 “loss” of function. The phase I-II clinical trial data of
two promising monoclonal antibodies to PCSK9, Alirocumab formerly SAR236553/REGN727and AMG145 will be