Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia - Brief Report

Maurizio Averna, Angelo Baldassare Cefalu', Aurélie Thedrez, Jorge Peter, Geesje Dallinga-Thie, Raul D. Santos, Angelo B. Cefalù, Barbara Sjouke, Maxime Passard, Mikael Croyal, Simon Prampart-Fauvet, Alexis Guédon, Maria Cossu, Milco Ciccarese, Alexis Guédon, Alexis Guédon, Livia Pisciotta, Paolo Pintus, Kees Hovingh, Milco CiccareseFrederick Raal, Maurizio Averna, Dirk Blom, Gilles Lambert

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)


Objective - Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)? Approach and Results - Primary lymphocytes were obtained from 28 genetically characterized ARH patients and 11 controls. ARH lymphocytes treated with mevastatin were incubated with increasing doses of recombinant PCSK9 with or without saturating concentrations of alirocumab. Cell surface LDL receptor expression measured by flow cytometry and confocal microscopy was higher in ARH than in control lymphocytes. PCSK9 significantly reduced LDL receptor expression in ARH lymphocytes albeit to a lower extent than in control lymphocytes (25% versus 76%, respectively), an effect reversed by alirocumab. Fluorescent LDL cellular uptake, also measured by flow cytometry, was reduced in ARH lymphocytes compared with control lymphocytes. PCSK9 significantly lowered LDL cellular uptake in ARH lymphocytes, on average by 18%, compared with a 46% reduction observed in control lymphocytes, an effect also reversed by alirocumab. Overall, the effects of recombinant PCSK9, and hence of alirocumab, on LDL receptor expression and function were significantly less pronounced in ARH than in control cells. Conclusions - PCSK9 inhibition with alirocumab on top of statin treatment has the potential to lower LDL cholesterol in some autosomal recessive hypercholesterolemia patients.
Original languageEnglish
Pages (from-to)1647-1650
Number of pages4
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Publication statusPublished - 2016

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine


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