Metabolic diseases such as hypercholesterolemia and cardiovascular disorders are among the diseases that weigh most heavily on humanity. They are one of the leading causes of death. In this field, the work of Dr. Nabil G. Seidah's team at the IRCM on the role of proprotein convertases has marked and continues to mark recent scientific history. Recently, the prestigious scientific journal Endocrine Reviews invited Dr. Nabil G. Seidah to provide an in-depth historical description of the discovery of the proprotein convertase PCSK9 and its involvement in certain cardiovascular diseases related to high LDLc levels (atherosclerosis, cardiac and metabolic diseases). The results of this work have just been published (PMID: 34626468) and offer a fascinating insight into the role of PCSK9, while providing hope for new therapeutic avenues for multiple other diseases.
We strongly believe that reducing PCSK9 levels will allow us to combat many of the diseases that affect our society. We have therefore summarized the different therapeutic approaches that are already being used clinically worldwide (including at the IRCM) such as the injection of monoclonal antibodies or antisense oligonucleotides against PCSK9. New approaches such as the use of the CRISPR methodology are in clinical phase-I since January 2022. The idea of being able to use these treatments in cancer and other diseases is by no means utopian, but could be realized in the near future, says Dr. Seidah.
The crucial role of proproteins convertases
Dr. Nabil G. Seidah, Director of the Biochemical Neuroendocrinology Research Unit at the IRCM, full professor in the Department of Medicine at the Université de Montréal and adjunct professor at the department of Experimental Medicine of McGill University, and winner of the 2011 Wilder-Penfield Award, has gained international recognition for highlighting the important functions of the nine members of the proprotein convertase family [PC1, PC2, Furin, PC4, PC5, PACE4, PC7, SKI-1/S1P and PCSK9], especially those of PCSK9. These convertases exert major physiological roles, and their dysregulation leads to various metabolic and neural pathologies, including cardiovascular diseases. PCSK9 is a clinical therapeutic target and is one of the most celebrated proteins of the last 15 years. While specific variants of PCSK9 were initially associated with a major cause of autosomal dominant hypercholesterolemia, PCSK9 inhibitors quickly became a source of hope for medical treatment for those affected by this disease or other cardiovascular disorders caused by excess circulating LDL cholesterol.
Over twenty-five years of research
The search for proteases (enzymes, convertases) responsible for the activation of secretory protein precursors (proprotein) generating hormones and bioactive proteins began in the early 1960s and led during the years 1990-2003 to the identification of a family of 9 proteases (7 of which were identified at the IRCM). They are therefore known as proprotein convertases (PC) related to bacterial subtilisin (S) and yeast kexin (K) (hence the acronym PCSK). This intensive search for maturation enzymes, which spanned more than 25 years until the discovery of the PCs, has led to a better understanding of the proprotein maturation process and its consequences. It has revealed the involvement of PCs in embryonic development and body homeostasis (the regulatory process by which the organism maintains the various constants of the internal environment), as well as their role in various pathologies, including cardiovascular and neurological diseases, but also cancer and the activation of certain infectious pathogens such as the viruses implicated in HIV and COVID-19 pathologies.
A little one that has made history and still raises a lot of hopes
PCSK9, the ninth and smallest member of the proprotein convertase family, was discovered and characterized at the IRCM leading to a major publication in February 2003 by Dr. Seidah's research group. The involvement of PCSK9 in the regulation of LDL-cholesterol (LDLc; the bad cholesterol) was then elaborated in June 2003 by this research team, in collaboration with a group of French scientists led by Dr Catherine Boileau. This ground-breaking work led to the development of a revolutionary new treatment to reduce circulating levels of LDLc that, in combination with statins, can reduce LDLc by 50-60%.
Moreover, new implications of PCSK9 in cancer/metastasis, sepsis, and inflammatory diseases have emerged in recent years, opening the door to novel clinical applications, for the better benefit of patients.
Acknowledgements
The close collaboration of the members of the IRCM group, including Drs. Annik Prat, Josée Hamelin, Suzanne Benjannet, Delia-Susan-Resiga and Rachid Essalmani, on the genetic and cellular levels, and Drs. Jean Davignon and Robert Dufour on the clinical level, were essential in this colossal work, that also included the contributions of Drs. Michel Chrétien and Majambu Mbikay, as well as the exceptional participation of Drs. Catherine Boileau and Marianne Abifadel, who opened the horizons of the discovery of PCSK9 and allowed a wide range of clinical applications of PCSK9 inhibitors.
This work was supported by the Canadian Institutes of Health Research (CIHR) and the Fondation Leduc.
