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

  • Genetics and Genomics (Ali Marian, Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

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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Acknowledgments

This work was supported by a grant from the Fondation Leducq (FLQ no. 13 CVD 03) through the Transatlantic Networks of Excellence in Cardiovascular Research program (“The function and regulation of PCSK9: a novel modulator of LDLR activity”), Institut National de la Santé et de la Recherche Médicale (INSERM), Conseil de la Recherche de l’Université Saint-Joseph (Beirut, Lebanon), and Conseil National de la Recherche Scientifique Libanais (CNRS-L).

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  1. Catherine Boileau and Marianne Abifadel contributed equally to this work.

Authors and Affiliations

  1. LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris Cedex 18, France

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

  2. Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie Santé, Saint Joseph University, Beirut, Lebanon

    Petra El Khoury, Sandy Elbitar, Youmna Ghaleb, Yara Abou Khalil & Marianne Abifadel

  3. Faculté de Médecine Paris 7, Université Denis Diderot, Paris, France

    Mathilde Varret & Catherine Boileau

  4. Département de Génétique, AP-HP, CHU Xavier Bichat, Paris, France

    Catherine Boileau

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  1. Petra El Khoury
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Correspondence to Catherine Boileau.

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Conflict of Interest

Marianne Abifadel and Catherine Boileau are consultants (advisory board or lecturers or research studies) for Amgen and Sanofi-Regeneron.

Petra El Khoury, Sandy Elbitar, Youmna Ghaleb, Yara Abou Khalil, and Mathilde Varret have nothing to disclose.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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El Khoury, P., Elbitar, S., Ghaleb, Y. et al. PCSK9 Mutations in Familial Hypercholesterolemia: from a Groundbreaking Discovery to Anti-PCSK9 Therapies. Curr Atheroscler Rep 19, 49 (2017). https://doi.org/10.1007/s11883-017-0684-8

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