One member of this family has garnered intense interest as a clinical drug target. As liver PCSK9 acts to maintain cholesterol homeostasis, it has become a target of intense interest for clinical drug development. Inhibition of PCSK9 can lower low-density cholesterol (LDL-C) by clearing LDLR-bound LDL particles, thereby lowering circulating cholesterol levels. It is hypothesised that this action may improve outcomes in patients with atherosclerotic cardiovascular disease [4-6]. Therapeutics which inhibit PCSK9 are viewed as potentially lucrative replacements for statins, upon statin patent expiry. Several monoclonal antibodies including alirocumab, evolocumab, bococizumab, RG-7652 and LY3015014 are under development. One RNAi therapeutic, code named ALN-PCS02, is also in development [1-3].

1. Cully M. (2013) Dyslipidaemia: RNAi targeting PCSK9 decreases lipid levels in a human trial. Nat Rev Cardiol, 10 (12): 682. [PMID:24145894]

2. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE, Hutabarat RM, Clausen VA, Karsten V, Cehelsky J et al.. (2014) Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet, 383 (9911): 60-8. [PMID:24094767]

3. Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, Butler D, Charisse K, Dorkin R, Fan Y et al.. (2008) Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci USA, 105 (33): 11915-20. [PMID:18695239]

4. Lopez D. (2008) Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia. Drug News Perspect, 21 (6): 323-30. [PMID:18836590]

5. Sahebkar A, Chew GT, Watts GF. (2014) Recent advances in pharmacotherapy for hypertriglyceridemia. Prog Lipid Res, 56: 47-66. [PMID:25083925]

6. Steinberg D, Witztum JL. (2009) Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels. Proc Natl Acad Sci USA, 106 (24): 9546-7. [PMID:19506257]