The function and regulation of PCSK9: a novel modulator of LDLR activity
- Bo Angelin, Karolinska Institute, Stockholm (Sweden)
- Nabil G. SEIDAH, IRCM, Montreal (Canada)
- Anders HAMSTEN, Karolinska Institute, Stockholm (Sweden)
- Robert DAY, University of Sherbrooke (Quebec)
- Yves DORY, University of Sherbrooke (Quebec)
- Guillaume PARE, McMaster University (Canada)
- Bertrand CARIOU, L’Institut du Thorax, Nantes (France)
- Marianne ABI-FADEL, Hopital Bichat-Claude Bernard-UMR1087 et NSFA, Paris (France)
This team of 17 scientists and clinicians from 6 distinct research centers in Canada, France and Sweden is dedicated to the comprehensive understanding of the biology of PCSK9 and its implication in hypercholesterolemia and cardiovascular disease (CVD). Elevated cholesterol levels fuel the atherosclerotic disease process that leads to CVD and premature death. Familial hypercholesterolemia, which affects 1 in 500 subjects worldwide, is known to be caused by genetic mutation. One of the most exciting developments in cardiovascular research in the last decade is the discovery in 2003 of PCSK9, an enzyme encoded by a gene whose mutations are associated with hypercholesterolemia. This relationship was established in French families by members of this team, and revealed an unsuspected regulatory component of the LDL receptor (LDLR). The role of PCSK9 in LDLR protein degradation in cells, animal models and humans signifies that its inhibition or suppression will be a powerful means of reducing LDL-cholesterol levels, and thus the burden of atherosclerosis and the incidence of CVD. Pharmaceutical companies are racing to develop PCSK9 inhibitors that may in the future substitute or complement the use of statins, especially in a setting of statin intolerance. Promising monoclonal PCSK9 antibody-based therapies that block PCSK9-LDLR interaction have now reached Phase-3 clinical trials, but there is still much to be learned about the biology of PCSK9, its regulation, its interacting proteins and genetics.
This research program will address many of the current knowledge gaps surrounding PCSK9 biology and is critical to develop new therapeutic approaches to achieve optimal serum LDL-cholesterol levels. Although highly valuable, this line of inquiry is not likely to be pursued by pharmaceutical companies, and can only be obtained by an international team of significant size, made up of multidisciplinary experts dedicated to the study of PCSK9, and its role in lipid metabolism. The knowledge gained will be put towards the development of therapeutics involving PCSK9 for people with high cholesterol levels and cardiovascular disease.