Aurélie Thedrez1, Barbara Sjouke1, Maxime Passard1, Simon Prampart-Fauvet1, Alexis Guédon1, Mikael Croyal1, Geesje Dallinga-Thie1, Jorge Peter1, Dirk Blom1, Milco Ciccarese1, Angelo B Cefalù1, Livia Pisciotta1, Raul D Santos1, Maurizio Averna1, Frederick Raal1, Paolo Pintus1, Maria Cossu1, Kees Hovingh1, Gilles Lambert1. 1. From the Inra UMR 1280, Université de Nantes, Faculté de Médecine, Nantes, France (A.T., M.P., S.P.-F., A.G., M.C., G.L.); Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands (B.S., G.D.-T., J.P., K.H.); Lipidology Division of Internal Medicine, University of Cape Town, Cape Town, South Africa (D.B.); Dipartimiento di Nefrologia Dialisi e Trapianto, SS Annunziata Hospital, Sassari, Italy (M.C., M.C.); University of Palermo, School of Medicine, Palermo, Italy (A.B.C., M.A.); University of Genoa, Genoa, Italy (L.P.); Lipid Clinic Heart Institute (InCor) University of Sao Paulo Medica School Hospital, Sao Paulo, Brazil (R.D.S.); Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa (F.R.); Dipartimento di Medicina Interna, Brotzu Hospital, Cagliari, Italy (P.P.); Inserm UMR 1188, Sainte Clotilde, France (G.L.); Université de la Réunion, Faculté de Médecine, Saint Denis de la Réunion, France (G.L.); and CHU de la Réunion, Saint-Denis de la Réunion, France (G.L.).
Abstract
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.
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 ARHpatients 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 hypercholesterolemiapatients.