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dc.contributor.authorBanerjee, Poulabi
dc.contributor.authorChan, Kuo-Chen
dc.contributor.authorTarabocchia, Michel
dc.contributor.authorBenito Vicente, Asier
dc.contributor.authorAlves, Ana C.
dc.contributor.authorBelloso Uribe, Kepa
dc.contributor.authorBourbon, Mafalda
dc.contributor.authorSkiba, Paul J.
dc.contributor.authorPordy, Robert
dc.contributor.authorGipe, Daniel A.
dc.contributor.authorGaudet, Daniel
dc.contributor.authorMartín Plágaro, César Augusto
dc.date.accessioned2020-01-24T09:08:22Z
dc.date.available2020-01-24T09:08:22Z
dc.date.issued2019-10-03
dc.identifier.citationArteriosclerosis Thrombosis and Vascular Biology 39(11) : 2248-2260 (2019)es_ES
dc.identifier.issn1079-5642
dc.identifier.issn1524-4636
dc.identifier.urihttp://hdl.handle.net/10810/39123
dc.description.abstractObjective: Homozygous familial hypercholesterolemia is a rare disease usually caused by LDLR (low-density lipoprotein receptor) mutations. Homozygous familial hypercholesterolemia is characterized by markedly elevated LDL-C (low-density lipoprotein cholesterol) levels and an extremely high risk of premature atherosclerotic cardiovascular disease. A phase 2, proof-of-concept study (NCT02265952) demonstrated that evinacumab, a fully human monoclonal antibody to ANGPTL3 (angiopoietin-like 3 protein), reduced LDL-C levels in 9 patients with genotypically confirmed homozygous familial hypercholesterolemia and was well tolerated. The aim of this study was to analyze the effects of evinacumab on LDLR activity in lymphocytes purified from patients in the proof-of-concept study. Approach and Results: LDLR activity was assessed in patient lymphocytes before and after treatment with evinacumab and versus lymphocytes carrying wild-type LDLR, and also in an LDLR-defective Chinese hamster ovary cell line (CHO-ldlA7) transfected with plasmids encoding the LDLR variants. Overall mean peak reduction in LDL-C with evinacumab was -58 +/- 18%, occurring between Week 4 and Week 12. Mutations identified in the 9 patients were shown to be pathogenic, with loss of LDLR activity versus wild type. Two of the LDLR variants, p.(Cys681*) and p.(Ala627Profs*38), were class 2 type mutations that are retained in the endoplasmic reticulum. Six variants were class 3 type mutations with impaired LDL-C binding activity: p.(Trp87Gly), occurring in 2 patients, p.(Gln254Pro), p.(Ser177Leu), p.(Gly335Val), and p.(Ser306Leu). Evinacumab had no effect on LDLR activity. Conclusions: These results suggest that evinacumab is effective for lowering LDL-C in patients with homozygous familial hypercholesterolemia, and the inhibition of ANGPTL3 in humans lowers LDL-C in a mechanism independent of the LDLR.es_ES
dc.description.sponsorshipThis analysis was funded by Regeneron Pharmaceuticals, Inc.es_ES
dc.language.isoenges_ES
dc.publisherLippincott Williams & Wilkinses_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es/*
dc.subjecthypercholesterolemiaes_ES
dc.subjectlipoproteinses_ES
dc.subjectmutationses_ES
dc.subjectproof of concept studyes_ES
dc.subjectrare diseasees_ES
dc.subjecttransmembrane domaines_ES
dc.subjectmonoclonal-antibodyes_ES
dc.subjectdouble-blindes_ES
dc.subjectamg 145es_ES
dc.subjectinhibitiones_ES
dc.subjectevolocumabes_ES
dc.subjectmutationses_ES
dc.subjectangptl3es_ES
dc.subjectpcsk9es_ES
dc.subjectgenees_ES
dc.titleFunctional Analysis of LDLR (Low-Density Lipoprotein Receptor) Variants in Patient Lymphocytes to Assess the Effect of Evinacumab in Homozygous Familial Hypercholesterolemia Patients With a Spectrum of LDLR Activityes_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.holder© 2019 The Authors. Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.es_ES
dc.rights.holderAtribución-NoComercial-SinDerivadas 3.0 España*
dc.relation.publisherversionhttps://www.ahajournals.org/doi/10.1161/ATVBAHA.119.313051es_ES
dc.identifier.doi10.1161/ATVBAHA.119.313051
dc.departamentoesBioquímica y biología moleculares_ES
dc.departamentoeuBiokimika eta biologia molekularraes_ES


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© 2019 The Authors. Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.
Except where otherwise noted, this item's license is described as © 2019 The Authors. Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.