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Expert Opin Investig Drugs. 2012 May;21(5):667-76. doi: 10.1517/13543784.2012.679340.

Inhibition of pro-protein convertase subtilisin kexin 9 [corrected] (PCSK-9) as a treatment for hyperlipidaemia.

Author information

1
St. Thomas' Hospital Campus, Department of Chemical Pathology , Lambeth Palace Road, London, UK. Anthony.Wierzbicki@kcl.ac.uk

Erratum in

  • Expert Opin Investig Drugs. 2012 Aug;21(8):1241.

Abstract

INTRODUCTION:

Pro-protein [corrected] convertase subtilisin kexin (PCSK)-9 is a newly discovered protein involved in intracellular and extracellular regulation of low-density lipoprotein receptor (LDLR) expression. Autosomal dominant activating mutations in PCSK-9 cause familial hypercholesterolaemia whereas inactivating mutations in man reduce LDL cholesterol (LDL-C) and are associated with a decreased lifetime risk of cardiovascular events.

AREAS COVERED:

As PCSK-9 binds to the LDLR, a number of approaches involving small molecule or peptide inhibition of binding, antibody-mediated inactivation of binding and the use of antisense oligonucleotides are being investigated as therapeutic approaches to lower LDL-C in man. This article reviews the biochemistry and physiology of PCSK-9 and details the efforts made to design novel molecules with the ability to inhibit PCSK-9 activity. Work in animal models has confirmed that reducing PCSK-9 expression can reduce atherosclerosis in mice, rats and primates. Monoclonal antibodies such as REGN-727 and AMG-145 have been shown to reduce LDL-C in patients with familial hypercholesterolaemia already treated with statins or healthy normocholesterolaemic controls.

EXPERT OPINION:

PCSK-9 inhibition is a potentially interesting novel addition to the armamentarium of LDL-C reducing drugs. Its effects in reducing LDL-C will need to be confirmed to reduce CVD events in large-scale clinical trials.

PMID:
22493980
DOI:
10.1517/13543784.2012.679340
[Indexed for MEDLINE]
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