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Ann Neurol. 2017 Aug;82(2):186-195. doi: 10.1002/ana.24987. Epub 2017 Jul 22.

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

Author information

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.

PMID:
28681388
DOI:
10.1002/ana.24987
[Indexed for MEDLINE]

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