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Current Atherosclerosis Reports
Published in: Current Atherosclerosis Reports 12/2017

01-12-2017 | Genetics and Genomics (Ali Marian, Section Editor)

PCSK9 Mutations in Familial Hypercholesterolemia: from a Groundbreaking Discovery to Anti-PCSK9 Therapies

Authors: Petra El Khoury, Sandy Elbitar, Youmna Ghaleb, Yara Abou Khalil, Mathilde Varret, Catherine Boileau, Marianne Abifadel

Published in: Current Atherosclerosis Reports | Issue 12/2017

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Abstract

Purpose of Review

In 2003, Abifadel et al. (Nat. Genet. 34:154–156, 2003) identified PCSK9, encoding proprotein convertase subtilisin/kexin type 9, as the third causal gene for autosomal dominant hypercholesterolemia. This review focuses on the main steps from this major breakthrough in familial hypercholesterolemia (FH) to the latest clinical trials with the anti-PCSK9 antibodies.

Recent Findings

The year 2015 was remarkable in cardiovascular disease through the field of cholesterol. Nearly 30 years after the discovery of statins, a new class of effective lipid-lowering drugs has emerged: the anti-PCSK9 antibodies. The discovery of the first gain-of-function mutations of PCSK9 in FH rapidly became the center of interest of researchers worldwide. Preclinical and clinical studies launched by pharmaceutical companies led to the first three anti-PCSK9 antibodies, two of which (evolocumab and alirocumab) reduce LDL cholesterol levels by 50–60% and received FDA and European Medicines Agency approvals in 2015 on top of statin therapy. Recently, results of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, the outcome trial of evolocumab over 2.2 years, showed a reduction of 15–20% in the risk of major cardiovascular outcomes in high-risk patients receiving statin therapy. Results of ODYSSEY OUTCOMES trial, evaluating the effect of alirocumab in 18,000 patients with established CVD are also eagerly awaited in 2018.

Summary

The evolution of research on PCSK9, starting from the discovery of the first set of mutations in PCSK9 in FH in 2003, is an amazing example of successful translational research. It shows how rigorous and powered genetic analyses can lead to the discovery of a new class of lipid-lowering drugs that give hope in fighting high cholesterol levels and their cardiovascular complications.
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Metadata
Title
PCSK9 Mutations in Familial Hypercholesterolemia: from a Groundbreaking Discovery to Anti-PCSK9 Therapies
Authors
Petra El Khoury
Sandy Elbitar
Youmna Ghaleb
Yara Abou Khalil
Mathilde Varret
Catherine Boileau
Marianne Abifadel
Publication date
01-12-2017
Publisher
Springer US
Published in
Current Atherosclerosis Reports / Issue 12/2017
Print ISSN: 1523-3804
Electronic ISSN: 1534-6242
DOI
https://doi.org/10.1007/s11883-017-0684-8

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