Targeting Chelatable Iron as a Therapeutic Modality in Parkinson ’ s Disease

Aims: The pathophysiological role of iron in Parkinson’s disease (PD) was assessed by a chelation strategy aimed at reducing oxidative damage associated with regional iron deposition without affecting circulating metals. Translational cell and animal models provided concept proofs and a delayed-start (DS) treatment paradigm, the basis for preliminary clinical assessments. Results: For translational studies, we assessed the effect of oxidative insults in mice systemically prechelated with deferiprone (DFP) by following motor functions, striatal dopamine (HPLC and MRIPET), and brain iron deposition (relaxation-R2*-MRI) aided by spectroscopic measurements of neuronal labile iron (with fluorescence-sensitive iron sensors) and oxidative damage by markers of protein, lipid, and DNA modification. DFP significantly reduced labile iron and biological damage in oxidation-stressed cells and animals, improving motor functions while raising striatal dopamine. For a pilot, double-blind, placebo-controlled randomized clinical trial, early-stage Parkinson’s patients on stabilized dopamine regimens enrolled in a 12-month single-center study with DFP (30mg/kg/day). Based on a 6-month DS paradigm, early-start patients (n 19) compared to DS patients (n 18) (37/40 completed) responded significantly earlier and sustainably to treatment in both substantia nigra iron deposits (R2* MRI) and Unified Parkinson’s Disease Rating Scale motor indicators of disease progression ( p<0.03 and p<0.04, respectively). Apart from three rapidly resolved neutropenia cases, safety was maintained throughout the trial. Innovation: Amoderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD. Conclusions: The therapeutic features of a chelation modality established in translational models and in pilot clinical trials warrant comprehensive evaluation of symptomatic and/or diseasemodifying potential of chelation in PD. Department of Medical Pharmacology, Faculté de Médecine Lille2, Lille Nord de France University, CHU Lille, Lille, France. Department of Movement Disorders and Neurology, Lille Nord de France University, CHU Lille, Lille, France. EA 1046, Lille Nord de France University, Lille, France. University of the Littoral, Lille Nord de France University, Lille, France. Unit 837 Equipe 4 Inserm and Faculté de Médecine, Lille Nord de France University, Lille, France. Department of Toxicology, Public Health and Environment, EA4483, Faculté des Sciences Pharmaceutiques et Biologiques de Lille, Lille, France. Departments of Molecular Biology, Biostatistics, and Neuroradiology, Lille Nord de France University, CHU Lille, Lille, France. Departments of Animal Neuroradiology and Animal Nuclear Medicine, Lille Nord de France University, Lille, France. Department of Pharmacology, APHP, Pitié Salpêtrière Hospital, Paris, France. INSERM U837/6 JPARC Université Lille Nord de France, Lille, France. INSERM, CR ICM, UMRS975, CNRS UMR7225, UPMC, INSERM, CIC 9503, Department of Neurology, Pitié Salpêtrière Hospital, Paris, France. Doerenkamp Zbinden Chair for In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz, Germany. Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany. Department of Hematology, Hôpital Saint Vincent de Paul, Lille Nord de France University, Lille, France. Della Pergola Chair, Alexander Silberman Institute of Life Sciences, Hebrew University, Jerusalem, Israel. *These authors contributed equally to this work.