MMP9 is decreased in natalizumab-treated MS patients at risk for PML

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 (RRMS) patients who developed PML under NTZ therapy (pre-PML) and non-PML natalizumab-treated patients (NTZ-ctr) were included in the study. Cryopreserved peripheral blood mononuclear cells (PBMC) and serum samples collected at baseline, at one- and two-year treated time points, and during PML were analyzed for gene expression by RNA-sequencing and for serum protein levels by LUMINEX and ELISA 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: pro-angiogenic 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 two-step manner in a screening cohort and a validation cohort of pre-PML and NTZ-ctr patients. Only MMP9 was validated and, 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 pro-angiogenic factor MMP9 may play a role as biomarker associated with the development of PML in MS patients treated with NTZ. This article is protected by copyright. All rights reserved.

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