Matrix metalloproteinase 9 is decreased in natalizumab-treated multiple sclerosis patients at risk for progressive multifocal leukoencephalopathy

Nicolas Fissolo, Béatrice Pignolet, Clara Matute-Blanch, Juan Carlos Triviño, Berta Miró, Miriam Mota, Santiago Perez-Hoyos, Alex Sanchez, Patrick Vermersch, Aurélie Ruet, Jérôme de Sèze, Pierre Labauge, Sandra Vukusic, Caroline Papeix, Laurent Almoyna, Ayman Tourbah, Pierre Clavelou, Thibault Moreau, Jean Pelletier, Christine Lebrun-FrenayXavier Montalban, David Brassat, Manuel Comabella

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11 Citations (Scopus)

Abstract

© 2017 American Neurological Association 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.
Original languageEnglish
Pages (from-to)186-195
JournalAnnals of Neurology
Volume82
Issue number2
DOIs
Publication statusPublished - 1 Aug 2017

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