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Proprotein convertase subtilisin/kexin type 9: from genetics to clinical trials

Stoekenbroek, Robert, M.; Kastelein, John, J.P.

Current Opinion in Cardiology: May 2018 - Volume 33 - Issue 3 - p 269–275
doi: 10.1097/HCO.0000000000000517
MOLECULAR GENETICS: Edited by Ali J. Marian

Purpose of review This review describes the pivotal role of genetic insights and technologies in the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the rapid development of PCSK9 inhibitors – a revolutionary new class of lipid-lowering agents.

Recent findings PCSK9 was discovered as a the third gene implicated in familial hypercholesterolemia. Population genetics studies, enabled by technological advances, were instrumental in validating PCSK9 as a therapeutic target. Monoclonal antibodies against PCSK9 were introduced in the clinic after an unprecedently rapid development path, in which clinical trial results confirmed that these drugs robustly lower cholesterol and improve clinical outcomes regardless of disease indication or background therapy. New strategies to PCSK9 inhibition are underway and have delivered promising preliminary results, including inhibition of PCSK9 synthesis by targeting the cellular gene expression machinery and vaccination. The future will tell whether directly targeting the genome through editing techniques will ultimately enable us to virtually eliminate many of the traditional CVD risk factors.

Summary The extraordinary PCSK9 narrative highlights the opportunities offered by genetics-driven drug development and holds valuable lessons for future development programs.

Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

Correspondence to John J.P. Kastelein, MD, PhD, Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1100DD Amsterdam, The Netherlands. Tel: +31 20 566 9111; e-mail:

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