학술논문
Hydroxychloroquine sulfate: A novel treatment for lipin-1 deficiency?
Document Type
Academic Journal
Author
Renard P; Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France.; Caccavelli L; Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France; Centre de référence des maladies héréditaires du métabolisme, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Institut Imagine, Filière G2M, MetabERN, F-75015 Paris, France.; Legendre A; Centre de référence Malformations Cardiaques Congénitales Complexes M3C - Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), F-75015 Paris, France.; Tuchmann-Durand C; Centre de référence des maladies héréditaires du métabolisme, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Institut Imagine, Filière G2M, MetabERN, F-75015 Paris, France; Institut Imagine, Centre d'Investigation Clinique pour les Thérapies innovantes, Département de Biothérapie, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), F-75015 Paris, France.; Balakirouchenane D; Département de pharmacocinétique et pharmacochimie, Centre Hospitalier Universitaire Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), CARPEM, F-75014 Paris, France.; Blanchet B; Département de pharmacocinétique et pharmacochimie, Centre Hospitalier Universitaire Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), CARPEM, F-75014 Paris, France; Université Paris Cité, PRES Sorbonne Paris Cité, CARPEM, Faculté de Pharmacie, INSERM U-1268 / CNRS UMR-8038, FR-750006 Paris, France.; Narjoz C; Service de Biochimie, Hôpital Universitaire Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (AP-HP), F-75015 Paris, France.; Straube M; Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France; Centre de référence des maladies héréditaires du métabolisme, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Institut Imagine, Filière G2M, MetabERN, F-75015 Paris, France.; Hubas A; Service de biochimie et Génétique Moléculaire, Laboratoire de culture cellulaire, Hôpital Universitaire Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), F-75014 Paris, France.; Garros A; Centre de compétence des maladies héréditaires du métabolisme, Hôpital Universitaire Grenoble Alpes, Filière G2M, Grenoble, France.; Mention K; Centre de référence des maladies héréditaires du métabolisme, Hôpital Universitaire Jeanne de Flandre, Filière G2M, MetabERN, Lille, France.; Bednarek N; Centre de compétence des maladies héréditaires du métabolisme, Hôpital Universitaire, Filière G2M, Reims, France.; Goudin N; Cell Imaging & Flow Cytometry Core Facilities, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, Paris, France.; Broissand C; Service de Pharmacie, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), F-75015 Paris, France.; Schlatter J; Service de Pharmacie, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), F-75015 Paris, France.; Cisternino S; Service de Pharmacie, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), F-75015 Paris, France; Université Paris Cité, Optimisation Thérapeutique en Neuropsychopharmacologie, INSERM UMRS-1144, F-75006 Paris, France.; Cagnard N; Université Paris Cité, Bioinformatiques, SFR Necker, INSERM US-24 / CNRS UAR-3633, F-75015 Paris, France.; van Endert P; Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France; Service Immunologie Biologique, AP-HP, Hôpital Universitaire Necker-Enfants Malades, F-75015 Paris, France.; Diana J; Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France.; de Calbiac H; Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France; Centre de référence des maladies héréditaires du métabolisme, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Institut Imagine, Filière G2M, MetabERN, F-75015 Paris, France.; de Lonlay P; Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, F-75015 Paris, France; Centre de référence des maladies héréditaires du métabolisme, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Institut Imagine, Filière G2M, MetabERN, F-75015 Paris, France. Electronic address: pascale.delonlay@aphp.fr.
Source
Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 8213295 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1950-6007 (Electronic) Linking ISSN: 07533322 NLM ISO Abbreviation: Biomed Pharmacother Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Lipin-1 deficiency is a life-threatening disease that causes severe rhabdomyolysis (RM) and chronic symptoms associated with oxidative stress. In the absence of treatment, Hydroxychloroquine sulfate (HCQ) was administered to patients off label use on a compassionate basis in order to improve their physical conditions.
Methods: Eleven patients with LPIN1 mutations were treated with HCQ. Clinical and biological efficacy and tolerance were assessed, including pain and quality of life, physical capacities, cardiopulmonary parameters, creatine kinase levels and plasma proinflammatory cytokines. To explore a dose-dependent effect of HCQ, primary myoblasts from 4 patients were incubated with various HCQ concentrations in growth medium (GM) or during starvation (EBSS medium) to investigate autophagy and oxidative stress.
Findings: Under HCQ treatment, patient physical capacities improved. Abnormal cardiac function and peripheral muscle adaptation to exercise were normalized. However, two patients who had the highest mean blood HCQ concentrations experienced RM. We hypothesized that HCQ exerts deleterious effects at high concentrations by blocking autophagy, and beneficial effects on oxidative stress at low concentrations. We confirmed in primary myoblasts from 4 patients that high in vitro HCQ concentration (10 µM) but not low concentration (1 µM and 0.1 µM) induced autophagy blockage by modifying endolysosomal pH. Low HCQ concentration (1 µM) prevented reactive oxygen species (ROS) and oxidized DNA accumulation in myoblasts during starvation.
Interpretation: HCQ improves the condition of patients with lipin-1 deficiency, but at low concentrations. In vitro, 1 µM HCQ decreases oxidative stress in myoblasts whereas higher concentrations have a deleterious effect by blocking autophagy.
Competing Interests: Declaration of Competing Interest PVE and PDL have filed PCT (WO/2017/085115; EP3377095; PCT/EP2016/077843) and US patent applications (US20180325890). PVE and PDL have filed PCT (WO/2019/020732; PCT/EP2018/070256) patent applications. The remaining authors have no competing interests.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Methods: Eleven patients with LPIN1 mutations were treated with HCQ. Clinical and biological efficacy and tolerance were assessed, including pain and quality of life, physical capacities, cardiopulmonary parameters, creatine kinase levels and plasma proinflammatory cytokines. To explore a dose-dependent effect of HCQ, primary myoblasts from 4 patients were incubated with various HCQ concentrations in growth medium (GM) or during starvation (EBSS medium) to investigate autophagy and oxidative stress.
Findings: Under HCQ treatment, patient physical capacities improved. Abnormal cardiac function and peripheral muscle adaptation to exercise were normalized. However, two patients who had the highest mean blood HCQ concentrations experienced RM. We hypothesized that HCQ exerts deleterious effects at high concentrations by blocking autophagy, and beneficial effects on oxidative stress at low concentrations. We confirmed in primary myoblasts from 4 patients that high in vitro HCQ concentration (10 µM) but not low concentration (1 µM and 0.1 µM) induced autophagy blockage by modifying endolysosomal pH. Low HCQ concentration (1 µM) prevented reactive oxygen species (ROS) and oxidized DNA accumulation in myoblasts during starvation.
Interpretation: HCQ improves the condition of patients with lipin-1 deficiency, but at low concentrations. In vitro, 1 µM HCQ decreases oxidative stress in myoblasts whereas higher concentrations have a deleterious effect by blocking autophagy.
Competing Interests: Declaration of Competing Interest PVE and PDL have filed PCT (WO/2017/085115; EP3377095; PCT/EP2016/077843) and US patent applications (US20180325890). PVE and PDL have filed PCT (WO/2019/020732; PCT/EP2018/070256) patent applications. The remaining authors have no competing interests.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)