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

ObjectiveTo identify biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ). MethodsRelapsing–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. ResultsAmong 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. InterpretationThe results from this study suggest that th...
Source: Annals of Neurology - Category: Neurology Authors: Tags: Research Article Source Type: research