Nicolas Fissolo1, Béatrice Pignolet2, Clara Matute-Blanch1, Juan Carlos Triviño3, Berta Miró4, Miriam Mota4, Santiago Perez-Hoyos4, Alex Sanchez4,5, Patrick Vermersch6, Aurélie Ruet7, Jérôme de Sèze8, Pierre Labauge9, Sandra Vukusic10, Caroline Papeix11, Laurent Almoyna12, Ayman Tourbah13, Pierre Clavelou14, Thibault Moreau15, Jean Pelletier16, Christine Lebrun-Frenay17, Xavier Montalban1, David Brassat2, Manuel Comabella1. 1. Department of Neurology-Neuroimmunology, Multiple Sclerosis Center of Catalonia, Vall d'Hebron Research Institute, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain. 2. Neurosciences Pole, Toulouse University Hospital Center, Physiopathology Center of Toulouse-Purpan, National Institute of Health and Medical Research, University of Toulouse, and Paul Sabatier University, Toulouse, France. 3. Genomic Systems, Valencia, Spain. 4. Statistics and Bioinformatics Unit, Vall d'Hebron Research Institute, Barcelona, Spain. 5. Department of Genetics, Microbiology, and Statistics, University of Barcelona, Barcelona, Spain. 6. Lilly University, Lille University Hospital Center, Lille Inflammation Research International Center, National Institute of Health and Medical Research, Immune-Mediated Inflammatory Diseases and Targeted Therapies Federal Hospital University Project, Lille, France. 7. Bordeaux University Hospital Center, National Institute of Health and Medical Research, Neurology Services, and Magendie Neurocenter, Bordeaux, France. 8. Department of Neurology, Civil Hospital, Strasbourg, France. 9. Department of Neurology, Montpellier University Hospital Center, France. 10. Department of Neurology, Lyon University Hospital Center, Bron, France. 11. Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France. 12. Chi Aix-en-Provence, Aix-en-Provence, France. 13. Department of Neurology and Reims Faculty of Medicine, Reims University Hospital Center, University of Reims Champagne-Ardenne, Reims, and University of Paris VIII, Saint-Denis, France. 14. Department of Neurology, Clermont-Ferrand Regional University Hospital Center, Clermont-Ferrand, France. 15. Department of Neurology, Dijon University Hospital Center, Dijon, France. 16. Aix-Marseille University, Public Assistance Hospitals of Marseilles, Timone Hospital, Clinical Neurosciences Pole, Neurology Service, National Center for Scientific Research, Biological and Medical Magnetic Resonance Center, Marseille, France. 17. Neurology Service, Pasteur Hospital, Nice, France.
Abstract
OBJECTIVE: To identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ). METHODS: Relapsing-remitting MS patients who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells and serum samples collected at baseline, at 1- and 2-year treated time points, and during PML were analyzed for gene expression by RNA sequencing and for serum protein levels by Luminex and enzyme-linked immunosorbent assays, respectively. RESULTS: Among top differentially expressed genes in the RNA sequencing between pre-PML and NTZ-ctr patients, pathway analysis revealed a high representation of genes belonging to the following categories: proangiogenic factors (MMP9, VEGFA), chemokines (CXCL1, CXCL5, IL8, CCL2), cytokines (IL1B, IFNG), and plasminogen- and coagulation-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD). Serum protein levels for these candidates were measured in a 2-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctr patients. Only matrix metalloproteinase 9 (MMP9) was validated; in pre-PML patients, MMP9 protein levels were significantly reduced at baseline compared with NTZ-ctr patients, and levels remained lower at later time points during NTZ treatment. INTERPRETATION: The results from this study suggest that the proangiogenic factor MMP9 may play a role as a biomarker associated with the development of PML in MS patients treated with NTZ. Ann Neurol 2017;82:186-195.
OBJECTIVE: To identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ). METHODS: Relapsing-remitting MSpatients who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells and serum samples collected at baseline, at 1- and 2-year treated time points, and during PML were analyzed for gene expression by RNA sequencing and for serum protein levels by Luminex and enzyme-linked immunosorbent assays, respectively. RESULTS: Among top differentially expressed genes in the RNA sequencing between pre-PML and NTZ-ctrpatients, pathway analysis revealed a high representation of genes belonging to the following categories: proangiogenic factors (MMP9, VEGFA), chemokines (CXCL1, CXCL5, IL8, CCL2), cytokines (IL1B, IFNG), and plasminogen- and coagulation-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD). Serum protein levels for these candidates were measured in a 2-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctrpatients. Only matrix metalloproteinase 9 (MMP9) was validated; in pre-PML patients, MMP9 protein levels were significantly reduced at baseline compared with NTZ-ctrpatients, and levels remained lower at later time points during NTZ treatment. INTERPRETATION: The results from this study suggest that the proangiogenic factor MMP9 may play a role as a biomarker associated with the development of PML in MSpatients treated with NTZ. Ann Neurol 2017;82:186-195.
Authors: Alessandra Aldinucci; Elena Bonechi; Tiziana Biagioli; Anna M Repice; Mario M D'Elios; Lorenzo Emmi; Giacomo Emmi; Elena Silvestri; Alessandro Barilaro; Clara Ballerini Journal: Ann Clin Transl Neurol Date: 2018-03-10 Impact factor: 4.511
Authors: Marco Iannetta; Maria Antonella Zingaropoli; Tiziana Latronico; Ilaria Pati; Simona Pontecorvo; Carla Prezioso; Valeria Pietropaolo; Antonio Cortese; Marco Frontoni; Claudia D'Agostino; Ada Francia; Vincenzo Vullo; Claudio Maria Mastroianni; Grazia Maria Liuzzi; Maria Rosa Ciardi Journal: Sci Rep Date: 2019-01-22 Impact factor: 4.379