Abstract
The discovery and elucidation of the role of the low-density lipoprotein receptor (LDL-R) in familial hypercholesterolemia (FH) ushered in the statin group of drugs. These drugs, in addition to lowering low-density lipoprotein cholesterol (LDL-C), result in a significant reduction in cardiovascular events (CVE) and mortality. Recently, a gain-of-function mutation in another protein, proprotein convertase subtilisin/kexin type 9 (PCSK9), was reported to result in a FH phenotype by promoting degradation of the LDL-R. More importantly, loss-of-function mutations in the same gene resulted in low LDL-C and a reduction in CVE, making this an enticing target for drug development. Numerous strategies have been developed to target PCSK9, the most successful being monoclonal antibodies (mAbs) that bind PCSK9. These mAbs have been shown to reduce LDL-C around 50% as either monotherapy with diet or in combination with statin therapy. In this short perspective, we discuss the biochemistry and biology of PCSK9 in relation to lipid metabolism and the promising studies in humans demonstrating a substantial reduction in LDL-C with relative good short-term safety of PCSK9 mAbs.
References
Oct 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·T L InnerarityS M Grundy
Apr 17, 1999·American Journal of Human Genetics·M VarretC Boileau
Apr 15, 2000·Arteriosclerosis, Thrombosis, and Vascular Biology·S C HuntM E Samuels
Jan 29, 2003·Proceedings of the National Academy of Sciences of the United States of America·Nabil G SeidahMichel Chretien
May 6, 2003·Nature Genetics·Marianne AbifadelCatherine Boileau
Jun 5, 2004·Arteriosclerosis, Thrombosis, and Vascular Biology·Geneviève DubucAnnik Prat
Jan 18, 2005·Nature Genetics·Jonathan CohenHelen H Hobbs
Jan 29, 2005·Proceedings of the National Academy of Sciences of the United States of America·Kara N MaxwellJan L Breslow
Aug 2, 2005·Cell Metabolism·Alan D Attie, Nabil G Seidah
Mar 24, 2006·The New England Journal of Medicine·Jonathan C CohenHelen H Hobbs
Nov 1, 2008·Journal of Lipid Research·Michael S Brown, Joseph L Goldstein
Nov 7, 2012·JAMA : the Journal of the American Medical Association·David SullivanEvan A Stein
Sep 10, 2013·Circulation·Evan A SteinFrederick J Raal
Nov 21, 2013·Circulation·Michael J KorenUNKNOWN OSLER Investigators
Jan 1, 2014·Archives of Cardiovascular Diseases·Michel Farnier
Jan 16, 2014·Annual Review of Medicine·Evan A Stein, Frederick Raal
Apr 1, 2014·The New England Journal of Medicine·Dirk J BlomUNKNOWN DESCARTES Investigators
May 20, 2014·American Journal of Clinical Pathology·Ishwarlal Jialal
Jun 25, 2014·Nature Reviews. Cardiology·Razvan T Dadu, Christie M Ballantyne
Jul 24, 2014·Current Atherosclerosis Reports·Marianne AbifadelCatherine Boileau