Abstract
Focal iron accumulation associated with brain iron dyshomeostasis is a pathological hallmark of various neurodegenerative diseases (NDD). The application of iron-sensitive sequences in magnetic resonance imaging has provided a useful tool to identify the underlying NDD pathology. In the three major NDD, degeneration occurs in central nervous system (CNS) regions associated with memory (Alzheimer’s disease, AD), automaticity (Parkinson’s disease, PD) and motor function (amyotrophic lateral sclerosis, ALS), all of which require a high oxygen demand for harnessing neuronal energy. In PD, a progressive degeneration of the substantia nigra pars compacta (SNc) is associated with the appearance of siderotic foci, largely caused by increased labile iron levels resulting from an imbalance between cell iron import, storage and export. At a molecular level, α-synuclein regulates dopamine and iron transport with PD-associated mutations in this protein causing functional disruption to these processes. Equally, in ALS, an early iron accumulation is present in neurons of the cortico-spinal motor pathway before neuropathology and secondary iron accumulation in microglia. High serum ferritin is an indicator of poor prognosis in ALS and the application of iron-sensitive sequences in magnetic resonance imaging has become a useful tool in identifying pathology. The molecular pathways that cascade down from such dyshomeostasis still remain to be fully elucidated but strong inroads have been made in recent years. Far from being a simple cause or consequence, it has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell-death pathway with unique lipoperoxidation signatures called ferroptosis. In turn, this has now provided insight into some key modulators of this cell-death pathway that could be therapeutic targets for the NDD. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. However, whilst chelators that strongly scavenge intracellular iron protect against oxidative neuronal damage in mammalian models and are proven to be effective in treating systemic siderosis, these compounds are not clinically suitable due to the high risk of developing iatrogenic iron depletion and ensuing anaemia. Instead, a moderate iron chelation modality that conserves systemic iron offers a novel therapeutic strategy for neuroprotection. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher affinity acceptors in cells or extracellular transferrin. Promising preclinical and clinical proof of concept trials has led to several current large randomized clinical trials that aim to demonstrate the efficacy and safety of conservative iron chelation for NDD, notably in a long-term treatment regimen.
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Acknowledgements
The authors wish to thank the support of the Lille University Hospital University of Lille, INSERM, the NS-Park/FCRIN clinical research network for Parkinson’s disease, the FILSAN network for amyotrophic lateral sclerosis, the French Ministry of Health (PHRC for FAIRALS-II study) the European commission for the grant N° 633190 of the H2020 program; NCT02655315 (FAIRPARK-II study), the DN2M regional fund. The authors also thank the Fédération de la Recherche Clinique du CHU de Lille, the French Charity France Parkinson, the French Charity ARLSA. The authors wish to than ApoPharma for providing deferiprone and advices for the investigator drive studies. FAIRPARK-II study group (with the support of the Lille University Hospital and NS-Park/FCRIN clinical research network, www.fairpark2.eu; funded by European commission grant N° 633190 of the H2020 program; NCT02655315). Abbruzzese Giovanni University of Genove Italy. Allain Marie-Anne ALLAIN CHU Lille France. Anheim Mathieu, Department of Movement Disorders and Neurology, NS-Park/FCRIN Network, CHU Strasbourg, Strasbourg, France. Bakker Martijn University Nijmegen Medical Center, Donders Institute Brain Cognition & Behaviour Center for Neurosciences The Netherland. Balzer-Geldsetzer Monika ipps University Hospital Essen, GermanyUniversitat Marburg. Bargalló Núria Magnetic Resonance Unit, Neurorradiology Section, Centre de Diagnòstic per la Imatge (CDI), IDIBAPS, Hospital Clínic, Barcelona, Catalonia, Spain. Barone Paolo University of Salerno Italy. Basenau Sandra, Philipps Universitat Marburg, Germany. Benchetrit Eve ICM, Hôpital Pitié-Salpêtrière, Paris, France. Berg Daniela, Department of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany. Bloem Bas University Nijmegen Medical Center, Donders Institute Brain Cognition & Behaviour Center for Neurosciences The Netherland. Boraud Thomas Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR CNRS 5293 and Department of Neurology, NS-Park/FCRIN Network, CHU de Bordeaux, Bordeaux, France. Bordet Regis, University de Lille, CHU de Lille, INSERM UMRS_1171, Service de Pharmacologie Clinique LICEND COEN Center Lille, France. Bouca Raquel Instituto de Medicina Molecular Lisboa Portugal. Bourdain Frédéric, Hôpital Foch, Suresnes, France. Bouzas Jimena European Clinical Research Infrastructure Network-ERIC, France. Brefel-Courbon Christine, CHU de Toulouse, INSERM; Centre d’Investigation Clinique CIC1436, Services de Neurologie et de Pharmacologie Clinique, NS-Park/FCRIN Network, Toulouse, France. Bubenheim Michael CHU-Hôpitaux de Rouen France. Burn David, Faculty of Medical Sciences Newcastle University United Kingdom. Bush Ashley I., Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia. Cabantchik Ioav, Della Pergola Chair, Alexander Silberman Institute of Life Sciences, Hebrew University, Jerusalem, 91,904, Israel. Calvas Fabienne, CHU de Toulouse, INSERM; Centre d’Investigation Clinique CIC1436, Services de Neurologie et de Pharmacologie Clinique, NS-Park/FCRIN Network, Toulouse, France. Cámara Ana Parkinson’s disease & Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, CIBERNED, Barcelona, Catalonia, Spain. Carrière Nicolas, University de Lille, CHU de Lille, INSERM UMRS_1171, Service de Neurologie NS-Park/FCRIN Network LICEND COEN Center Lille, France. Chaigneau Véronique, NS-Park/FCRIN Network, Toulouse, France. Compta Yaroslau, Parkinson’s disease & Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, IDIBAPS Barcelona, Catalonia, Spain. Connelly John, ApoPharma Inc., Toronto, Canada. Cormier-Dequaire Florence Hôpital Pitié-Salpêtrière, Paris, France. Corvol Jean-Christophe, Sorbonne Universités, UPMC Univ Paris 06, and INSERM UMRS_1127 and CIC_1422, and CNRS UMR_7225, and AP-HP, and ICM, Hôpital Pitié-Salpêtrière, NS-Park/FCRIN Network, Département des maladies du système nerveux, Paris, France. Cranston Amy University of Newcastle upon Tyne UK. De Bie Rob, Academisch Medisch Centrum Universiteit van Amsterdam.Amsterdam, Netherlands. De Marzi Roberto, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. Defebvre Luc, University de Lille, CHU de Lille, INSERM UMRS_1171, Service de Neurologie NS-Park/FCRIN Network LICEND COEN Center Lille, France. Degos Bertrand Hôpital Pitié-Salpêtrière, Paris, France. Demotes Jacques, European Clinical Research Infrastructure Network-ERIC, France. Dellapina Estelle, NS-Park/FCRIN Network, Toulouse, France. Deplanque Dominique, University de Lille, CHU de Lille, INSERM UMRS_1171, Service de Pharmacologie Clinique et CIC-CHU Lille, LICEND COEN Center Lille, France. Devedjian Jean-Christophe, University de Lille, CHU de Lille, INSERM UMRS_1171, NS-Park/FCRIN Network LICEND COEN Center Lille, France. Devos David, University de Lille, CHU de Lille, INSERM UMRS_1171, Service de Pharmacologie Clinique et service de Neurologie NS-Park/FCRIN Network LICEND COEN Center Lille, France. Dexter David, Imperial College London London United Kingdom. Dodel Richard, University Hospital Essen, GermanyPhilipps Universitat Marburg Germany. Dongmo Carole Hôpital Pitié-Salpêtrière, Paris, France. Duce James, School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, West Yorkshire, UK & Oxidation Biology Unit, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia. Duhamel Alain, CHU Lille France. Dupouy Julia, CHU de Toulouse, INSERM; Centre d’Investigation Clinique CIC1436, Services de Neurologie et de Pharmacologie Clinique, NS-Park/FCRIN Network, Toulouse, France. Durif Franck, Department of Movement Disorders and Neurology, NS-Park/FCRIN Network, CHU Clermont-Ferrand, Clermont-Ferrand, France. Dusek Petr, Dept. of Neurology, Charles University, Prague, Czech Republic. Eusebio Alexandre, Department of Neurology and Movement Disorders – APHM Timone University Hospital and Institut de Neurosciences de la Timone, NS-Park/FCRIN Network, AMU-CNRS UMR 7289, Marseille, France. Eyvrard Frédéric, Pharmacy, CHU de Toulouse, Toulouse, France. Fernández Manel Parkinson’s disease & Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, CIBERNED, Barcelona, Catalonia, Spain. Ferreira Joaquim, Instituto de Medicina Molecular Lisboa Portugal. Forni Gian Luca, Ospedia Galliera Italy. Foubert-Samier Alexandra Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR CNRS 5293 and Department of Neurology, NS-Park/FCRIN Network, CHU de Bordeaux, Bordeaux, France. Fradette Caroline, ApoPharma Inc., Toronto, Canada. Fréville Laëtitia, Centre pour l’Acquisition et le Traitement des Images (www.cati-neuroimaging.com); Sorbonne Universités, UPMC Univ Paris 06, CNRS, INSERM, Laboratoire d’Imagerie Biomédicale, F-75013, Paris, France. Galitzky Monique, CHU de Toulouse, INSERM; Centre d’Investigation Clinique CIC1436, Services de Neurologie et de Pharmacologie Clinique, NS-Park/FCRIN Network, Toulouse, France. Gaudebout Cecile Hôpital Pitié-Salpêtrière, Paris, France. Gelé Patrick CHU de Lille CHU Lille France. Giladi Nir Tel Aviv Sourasky Medical Center Israel. Grabli David Hôpital Pitié-Salpêtrière, Paris, France. Grolez Guillaume University de Lille, CHU de Lille, INSERM UMRS_1171, Service de Neurologie NS-Park/FCRIN Network LICEND COEN Center Lille, France. Guyon Pauline CHU Lille France. Habert Marie-Odile, Sorbonne Universités, UPMC Univ Paris 06, CNRS, INSERM, Laboratoire d’Imagerie Biomédicale, AP-HP, Hôpital Pitié-Salpêtrière, Département de Médecine Nucléaire, F-75013, Paris, France. Harroch Estelle, CHU de Toulouse, INSERM; Centre d’Investigation Clinique CIC1436, Services de Neurologie et de Pharmacologie Clinique, Toulouse, France. Hartmann Andreas Hôpital Pitié-Salpêtrière, Paris, France. Hirsch Denise, INSERM - Transfert SA Paris. Hopfner Franziska Department of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany. Jurado Camille, Pharmacy, CHU de Toulouse, Toulouse, France. Kaiser Andreas Medizinische Universitat Innsbruck Austria. Klaus Seppi Medizinische Universitat Innsbruck. Kouassi Nadège, CHU de Toulouse, INSERM; Centre d’Investigation Clinique CIC1436, Services de Neurologie et de Pharmacologie Clinique, Toulouse, France. Labreuch Julien CHU de Lille CHU Lille France. Lacomblez Lucette Hôpital Pitié-Salpêtrière, Paris, France. Lanthaler Barbara Medizinische Universitat Innsbruck Austria. Le Forestier Nadine Assistance Publique – Hôpitaux de Paris France. Le Naour Stéphanie INSERM - Transfert SA Paris France. Le Toullec Benjamin Hôpital Pitié-Salpêtrière, Paris, France. Locatelli Maxime, Centre pour l’Acquisition et le Traitement des Images (www.cati-neuroimaging.com); ICM Institut du Cerveau et de la Moelle épinière, CNRS UMR7225, INSERM U1127, UPMC, F-75013, Paris, France. Lomeña Francisco Nuclear Medicine Department, Hospital Clíınic, IDIBAPS, University of Barcelona, CIBERSAM, Barcelona, Catalonia, Spain. Longato Nadine Department of Movement Disorders and Neurology, NS-Park/FCRIN Network, CHU Strasbourg, Strasbourg, France. Lützen Ulf Department of Nuclear Medicine, Molecular Diagnostic Imaging and Therapy, University Hospital of Schleswig–Holstein (UKSH), Campus Kiel, Germany. Maetzler Corina Department of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany. Maetzler Walter, Department of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany. Mahlknecht Philipp Medizinische Universitat Innsbruck Austria. Mangone Graziella Hôpital Pitié-Salpêtrière, Paris, France. Mariani Louise-Laure Hôpital Pitié-Salpêtrière, Paris, France. Marques Ana, Department of Movement Disorders and Neurology, NS-Park/FCRIN Network, CHU Clermont-Ferrand, Clermont-Ferrand, France. Matthias Löhle, MD, Department of Neurology, University of Rostock, Rostock, Germany. Meissner Wassilios G., Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR CNRS 5293 and Department of Neurology, NS-Park/FCRIN Network, CHU de Bordeaux, Bordeaux, France. Michon Amelie, European Clinical Research Infrastructure Network-ERIC, France. Moreau Caroline, University de Lille, CHU de Lille, INSERM UMRS_1171, Service de Neurologie NS-Park/FCRIN Network LICEND COEN Center Lille, France. Nardocci Nardo Nardocci Istitu Besta Italy. Nosal Florence CHU de Lille France. Nyholm Dag Uppsala University Sweden. Oeckl Patrick Universitaet Ulm Germany. Ory Fabienne, CHU de Toulouse, INSERM; Centre d’Investigation Clinique CIC1436, Services de Neurologie et de Pharmacologie Clinique, Toulouse, France. Otto Markus, Universitaet Ulm Germany. Ouk Thavarak University de Lille, CHU de Lille, INSERM UMRS_1171, Service de Neurologie NS-Park/FCRIN Network LICEND COEN Center Lille, France. Pavese Nicola University of Newcastle upon Tyne UK. Peball Marina Medizinische Universitat Innsbruck Austria. Phillips Clélie Department of Movement Disorders and Neurology, NS-Park/FCRIN Network, CHU Strasbourg, Strasbourg, France. Pineau Fanny Hôpital Pitié-Salpêtrière, Paris, France. Planellas Lluís Parkinson’s disease & Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, CIBERNED, Barcelona, Catalonia, Spain. Poewe Werner, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. Pop-Ilieva Lydia, ApoPharma Inc., Toronto, Canada. Post Bart, Radboud University Nijmegen Medical Center, Donders Institute Brain Cognition & Behaviour Center for Neurosciences The Netherland. Rabier Aurélie Inserm NS-Park/FCRIN Network, Toulouse, France. Rascol Olivier, Université de Toulouse, UPS, CHU de Toulouse, INSERM; Centre d’Investigation Clinique CIC1436, Services de Neurologie et de Pharmacologie Clinique, UMR TONIC, NS-Park/FCRIN Network, NeuroToul COEN Center, Toulouse, France. Riedel Christian Department of Neuroradiology, Christian-Albrechts University, Kiel, Germany. Rodrigues Maura Hôpital Pitié-Salpêtrière, Paris, France. Rose Christian Hopital Saint-Vincent-de-Paul Lille France. Roullet-Solignac Isabelle Movement Disorders Unit, Hopital Neurologique, Hospices Civils de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, CNRS Institut des Sciences Cognitives, Centre de Neurosciences, Cognitives, UMR 5229, NS-Park/FCRIN Network, Bron Lyon France. Rozova Anna, ApoPharma Inc., Toronto, Canada. Růžička Evžen, Dept. of Neurology, Charles University, Prague, Czech Republic. Salis Alexandra, Inserm NS-Park/FCRIN Network, Toulouse, France. Schäffer Eva Department of Neurology, University Hospital Schleswig–Holstein, Christian-Albrechts University Kiel, Germany. Scherfler Christoph Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. Schiefermeier Natalia, Department of Neurology, Medical University Innsbruck, Innsbruck, AustriaSeppi Klaus Department of Neurology, Medical University Innsbruck, Innsbruck, AustriaSmagghe Delphine, INSERM - Transfert SA Paris France. Silva Tânia, Instituto de Medicina Molecular Lisboa Portugal. Socha Julie Hôpital Pitié-Salpêtrière, Paris, France. Souyris Corinne, CHU de Toulouse, INSERM; Centre d’Investigation Clinique CIC1436, Services de Neurologie et de Pharmacologie Clinique, Toulouse, France. Spampinato Umberto Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR CNRS 5293 and Department of Neurology, NS-Park/FCRIN Network, CHU de Bordeaux, Bordeaux, France. Spino Michael, ApoPharma Inc., Toronto, Canada. Steel Alison University of Newcastle upon Tyne UK. Sweta Bajaj Medizinische Universitat Innsbruck Austria. Thalamas Claire, CHU de Toulouse, INSERM; Centre d’Investigation Clinique CIC1436, Services de Neurologie et de Pharmacologie Clinique, Toulouse, France. Teodor Danaila Movement Disorders Unit, Hopital Neurologique, Hospices Civils de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, CNRS Institut des Sciences Cognitives, Centre de Neurosciences, Cognitives, UMR 5229, NS-Park/FCRIN Network, Bron Lyon France. Teresa Anna Instituto de Medicina Molecular Lisboa Portugal. Thibault Laetitia, CHU Lille France. Thobois Stéphane, Movement Disorders Unit, Hopital Neurologique, Hospices Civils de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, CNRS Institut des Sciences Cognitives, Centre de Neurosciences, Cognitives, UMR 5229, NS-Park/FCRIN Network, Bron Lyon FranceFrance. Tison François Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR CNRS 5293 and Department of Neurology, NS-Park/FCRIN Network, CHU de Bordeaux, Bordeaux, France. Tolosa Eduardo, Parkinson’s disease & Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, CIBERNED, Barcelona, Catalonia, Spain. Tranchant Christine, Department of Movement Disorders and Neurology, NS-Park/FCRIN Network, CHU Strasbourg, Strasbourg, France. Tricta Fernando, ApoPharma Inc., Toronto, Canada. Trifirò Gianluca Trifirò University of Messina & Erasmus Medical Center, Rotterdam The Netherlands. Uwe Walter, MD, Department of Neurology, University of Rostock, Rostock, Germany. Vidailhet Marie Hôpital Pitié-Salpêtrière, Paris, France. Wang Yi, PhD, Departments of Radiology and Biomedical Engineering, Cornell University, New York, USA. Werkmann Mario Medizinische Universitat Innsbruck Austria. Yilmas Rezzak Department of Neurology, University Hospital Schleswig–Holstein, Christian-Albrechts University Kiel, Germany. You Hana Hôpital Pitié-Salpêtrière, Paris, France. Zeuner Kirsten Department of Neurology, University Hospital Schleswig–Holstein, Christian-Albrechts University Kiel, Germany. The investigators of the 24 centres.
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(1) The research project: A: conception; B: organization; C: execution. (2) The manuscript: A: writing of the first draft, B. review and critical comment. DD: A1, B1, C1, A2, B2. IC: B1, C1, A2, B2. CM: C1, B2. VD: C1, B2. LMS: C1, B2. HB: C1, B2. FG: C1, A2, B2. ASR: B1, C1, A2, B2. JD: B1, C1, A2, B2. JCD: B1, C1, A2, B2
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The authors have no financial disclosures to make or potential conflicts of interest to report in relation to this study. The paper is referring to four academic studies including two translational studies already published : FAIRPARK-I (Efficacy and Safety of the Iron Chelator Deferiprone in Parkinson's Disease Protocol ID: 2008-006842-25; ClinicalTrials.gov: NCT00943748) and SAFEFAIR-ALS (Efficacy and Safety of the Iron Chelator Deferiprone in Amyotrophic lateral sclerosis Protocol ID: 2013-001228-21; ClinicalTrials.gov: NCT02164253) and two in progress : FAIRPARK-II (with the French NS-Park network, which is funded by a grant from the European Commission Horizon 2020 PHC13 2014-2015 (N° 633190): “Conservative iron chelation as a disease-modifying strategy in Parkinson’s disease: a multicentre, parallel-group, placebo-controlled, randomized clinical trial of deferiprone” Protocol ID: 2015_22; Clinical trial: NCT02655315 http://fairpark2.eu) and FAIRALS-II (Conservative Iron Chelation by Deferiprone as a Disease-modifying Strategy for Amyotrophic Lateral Sclerosis using a Multicentre, Parallel-group, Placebo-controlled, Randomized Clinical Trial on 240 patients. Protocol ID: 2017-003763-35; ClinicalTrials.gov: NCT03293069 funded by the French Ministry of Health, PHRC-N2017). ApoPharma provided deferiprone and advices on the molecule for the four investigator drive studies. Caroline Moreau has received grants from the France Parkinson charity. She has received various honoraria from pharmaceutical companies for consultancy and lectures on Parkinson’s disease at symposia such as Aguettant, Abbvie, Medtronic, Novartis. James Duce has received research funding from Alzheimer’s Society, Alzheimer’s Research UK, European Commission, Parkinson’s UK and NHMRC. He serves as a scientific advisor on the FAIRPARK II but has no financial disclosures. Ioav Cabantchik consults for Aferrix Ltd (Israel) and Hinoman (Ltd) Israel and has been an invited speaker in meetings organized by Apopharma (Canada) for which he received lecturer honoraria. David Devos has received PHRC grants from the French Ministry of Health and research funding from the ARSLA charity, France Parkinson charity, Credit Agricole Fundation. He has led two pilot investigator driven studies with DFP provided for free by ApoPharma (FAIRPARK-I and SAFE-FAIR ALS-I). He is leading two large investigator driven studies with DFP provided for free by ApoPharma (FAIRPARK-II and FAIR ALS-II). He served on advisory boards, served as a consultant and given lectures for pharmaceutical companies such as Orkyn, Everpharma, Abbvie, Boston Scientific, Lundbeck. Jean-Christophe Devedjian, Véronique Danel, Laura Mahoney-Sanchez, Hind Bouchaoui, Anne-Sophie Rolland have nothing to declare.
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Devos, D., Cabantchik, Z.I., Moreau, C. et al. Conservative iron chelation for neurodegenerative diseases such as Parkinson’s disease and amyotrophic lateral sclerosis. J Neural Transm 127, 189–203 (2020). https://doi.org/10.1007/s00702-019-02138-1
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DOI: https://doi.org/10.1007/s00702-019-02138-1