The promises of PCSK9 inhibition

Current Opinion in Lipidology

Volumn 24, Issue 4, 2013, Pages 307-312

  Petrides, Francine ^a   Shearston, Kate ^a   Chatelais, Mathias ^b   Guilbaud, Florian ^b   Meilhac, Olivier ^c   Lambert, Gilles ^a,b,d  

^a UNIVERSITY OF NEW SOUTH WALES   (Australia)

^b Universite de Nantes   (France)

^c BICHAT HOSPITAL   (France)

^d UNIVERSITÉ DE NANTES   (France)

Author keywords

Cardiovascular disease; Clinical trial; LDL receptor; Monoclonal antibodies; PCSK9

Indexed keywords

ALIROCUMAB; AMG 145; ATORVASTATIN; EZETIMIBE; HYPOCHOLESTEROLEMIC AGENT; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PLACEBO; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9; SUBTILISIN; UNCLASSIFIED DRUG;

COGNITIVE DEFECT; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; DYSLIPIDEMIA; ENZYME INHIBITION; ENZYME REGULATION; FAMILIAL HYPERCHOLESTEROLEMIA; HUMAN; HYPERCHOLESTEROLEMIA; LOW DRUG DOSE; PATIENT SAFETY; PRIORITY JOURNAL; PROTEIN FUNCTION; REVIEW;

ANIMALS; ANTIBODIES, MONOCLONAL; ANTICHOLESTEREMIC AGENTS; CLINICAL TRIALS, PHASE III AS TOPIC; GENE EXPRESSION REGULATION, ENZYMOLOGIC; HUMANS; HYPERCHOLESTEROLEMIA; PROPROTEIN CONVERTASES; SERINE ENDOPEPTIDASES;

EID: 84880607742     PISSN: 09579672     EISSN: 14736535     Source Type: Journal    
DOI: 10.1097/MOL.0b013e328361f62d     Document Type: Review

References (49)

1. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34:154-156.
2. Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 2005; 37:161-165.
3. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354:1264-1272.
4. Lambert G. Unravelling the functional significance of PCSK9. Curr Opin Lipidol 2007; 18:304-309.
5. Lambert G, Sjouke B, Choque B, et al. The PCSK9 decade. J Lipid Res 2012; 53:2515-2524.
6. Marais DA, Blom DJ, Petrides F, et al. Proprotein convertase subtilisin/kexin type 9 inhibition. Curr Opin Lipidol 2012; 23:511-517.
7. Mayne J, Dewpura T, Raymond A, et al. Novel loss-of-function PCSK9 variant is associated with low plasma LDL cholesterol in a French-Canadian family and with impaired processing and secretion in cell culture. Clin Chem 2011; 57:1415-1423.
8. Benjannet S, Hamelin J, Chretien M, Seidah NG. Loss- and gain-of-function PCSK9 variants: cleavage specificity, dominant negative effects, and low density lipoprotein receptor (LDLR) degradation. J Biol Chem 2012; 287:33745-33755.
9. Wang Y, Huang Y, Hobbs HH, Cohen JC. Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR. J Lipid Res 2012; 53:1932-1943.
10. Saavedra YG, Day R, Seidah NG. The M2 module of the Cys-His-rich domain (CHRD) of PCSK9 protein is needed for the extracellular low-density lipoprotein receptor (LDLR) degradation pathway. J Biol Chem 2012; 287:43492-43501.
11. Surdo PL, Bottomley MJ, Calzetta A, et al. Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH. EMBO Rep 2011; 12:1300-1305.
12. Tveten K, Holla OL, Cameron J, et al. Interaction between the ligand-binding domain of the LDL receptor and the C-terminal domain of PCSK9 is required for PCSK9 to remain bound to the LDL receptor during endosomal acidification. Hum Mol Genet 2012; 21:1402-1409.
13. Bottomley MJ, Cirillo A, Orsatti L, et al. Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants. J Biol Chem 2009; 284:1313-1323.
14. Poirier S, Mayer G, Poupon V, et al. Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route. J Biol Chem 2009; 284:28856-28864.
15. Ai X, Fischer P, Palyha OC, et al. Utilizing Halo Tag technology to track the fate of PCSK9 from intracellular vs. extracellular sources. Curr Chem Genom 2012; 6:38-47.
16. Scotti E, Calamai M, Goulbourne CN, et al. IDOL stimulates clathrin-independent endocytosis and MVB-mediated lysosomal degradation of the LDLR. Molec Cell Biol 2013; 33:1503-1514.
17. Kosenko T, Golder M, Leblond G, et al. Low-density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated LDL receptor degradation. J Biol Chem 2013; 288:8279-8288.
18. Cameron J, Bogsrud MP, Tveten K, et al. Serum levels of proprotein convertase subtilisin/kexin type 9 in subjects with familial hypercholesterolemia indicate that proprotein convertase subtilisin/kexin type 9 is cleared from plasma by low-density lipoprotein receptor-independent pathways. Transl Res 2012; 160:125-130.
19. Devay RM, Shelton DL, Liang H. Characterization of PCSK9 trafficking reveals a novel lysosomal targeting mechanism via APLP2. J Biol Chem 2013; 288:10805-10818.
20. Sun H, Samarghandi A, Zhang N, et al. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. Arterioscler Thromb Vasc Biol 2012; 32:1585-1595.
21. Awan Z, Seidah NG, Macfadyen JG, et al. Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial. Clin Chem 2012; 58:183-189.
22. Huijgen R, Boekholdt SM, Arsenault BJ, et al. Plasma PCSK9 levels and clinical outcomes in the TNT (Treating to New Targets) trial: a nested casecontrol study. J Am Coll Cardiol 2012; 59:1778-1784.
23. 'Melone M, Wilsie L, Palyha O, et al. Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9. J Am Coll Cardiol 2012; 59:1697-1705.
24. Kwakernaak AJ, Lambert G, Dullaart RP. Relationship of proprotein convertase subtilisin-kexin type 9 levels with resistin in lean and obese subjects. Clin Biochem 2012; 45:1522-1524.
25. Dong B, Wu M, Li H, et al. Strong induction of PCSK9 gene expression through HNF1alpha and SREBP2: mechanism for the resistance to LDLcholesterol lowering effect of statins in dyslipidemic hamsters. J Lipid Res 2010; 51:1486-1495.
26. Ai D, Chen C, Han S, et al. Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. J Clin Investig 2012; 122:1262-1270.
27. Le Bras M, Roquilly A, Deckert V, et al. Plasma PCSK9 is a late biomarker of severity in patients with severe trauma injury. J Clin Endocrinol Metab 2013; 98:E732-736.
28. Seidah NG, Poirier S, Denis M, et al. Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation. PloS One 2012; 7:e41865.
29. Essalmani R, Susan-Resiga D, Chamberland A, et al. In vivo evidence that furin from hepatocytes inactivates PCSK9. J Biol Chem 2011; 286:4257-4263.
30. Lipari MT, Li W, Moran P, et al. Furin-cleaved proprotein convertase subtilisin/kexin type 9 (PCSK9) is active and modulates low density lipoprotein receptor and serum cholesterol levels. J Biol Chem 2012; 287:43482-43491.
31. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012; 366:1108-1118.
32. McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012; 59:2344-2353.
33. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012; 380:29-36.
34. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012; 367:1891-1900.
35. Dias CS, Shaywitz AJ, Wasserman SM, et al. Effects of AMG 145 on lowdensity lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol 2012; 60:1888-1898.
36. Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterollowering effects of AMG145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 2012; 126:2408-2417.
37. Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. J Am Med Assoc 2012; 308:2497-2506.
38. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet 2012; 380:1995-2006.
39. Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet 2012; 380:2007-2017.
40. Huijgen R, Fouchier SW, Denoun M, et al. Plasma levels of PCSK9 and phenotypic variability in familial hypercholesterolemia. J Lipid Res 2012; 53:979-983.
41. Denis M, Marcinkiewicz J, Zaid A, et al. Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation 2012; 125:894-901.
42. Al-Mashhadi RH, Sorensen CB, Kragh PM, et al. Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. Sci Transl Med 2013; 5:166ra161.
43. Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 2007; 193:445-448.
44. Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006; 79:514-523.
45. Postmus I, Trompet S, de Craen AJ, et al. PCSK9 SNP rs11591147 is associated with low cholesterol levels but not with cognitive performance or noncardiovascular clinical events in an elderly population. J Lipid Res 2013; 54:561-566.
46. Sun X, Essalmani R, Day R, et al. Proprotein convertase subtilisin/kexin type 9 deficiency reduces melanoma metastasis in liver. Neoplasia 2012; 14:1122-1131.
47. Larosa JC, Pedersen TR, Somaratne R, Wasserman SM. Safety and effect of very low levels of low-density lipoprotein cholesterol on cardiovascular events. Am J Cardiol 2013; 111:1221-1229.
48. Sharotri V, Collier DM, Olson DR, et al. Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9). J Biol Chem 2012; 287:19266-19274.
49. Vincent FB, Morand EF, Murphy K, et al. Antidrug antibodies (ADAb) to TNFspecific neutralizing agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis 2013; 165-178.