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Matrix metalloproteinase 9 is decreased in natalizumab-treated multiple sclerosis patients at risk for progressive
Nicolas Fissolo1, Béatrice Pignolet2, Clara Matute-Blanch1
1Department of Neurology-Neuroimmunology, Multiple Sclerosis Center of Catalonia, Vall d'Hebron Research Institute, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain.
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.
Insights
Matrix metalloproteinase 9 (MMP9) may serve as a biomarker for progressive multifocal leukoencephalopathy (PML) risk in multiple sclerosis (MS) patients undergoing natalizumab (NTZ) treatment. Lower baseline MMP9 levels indicate increased PML development risk.
Area of Science:
- Neuroimmunology
- Biomarker Discovery
- Molecular Biology
Background:
- Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system.
- Natalizumab (NTZ) is an effective disease-modifying therapy for MS, but carries a risk of progressive multifocal leukoencephalopathy (PML).
- Identifying biomarkers for PML risk in NTZ-treated MS patients is crucial for patient safety.
Purpose of the Study:
- To identify novel biomarkers associated with the development of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab (NTZ).
Main Methods:
- Retrospective analysis of gene expression (RNA sequencing) and serum protein levels (Luminex, ELISA) in MS patients who developed PML (pre-PML) versus those who did not (NTZ-ctr) during NTZ therapy.
- Samples were collected at baseline, 1- and 2-year treatment points, and during PML.
- Pathway analysis of differentially expressed genes focused on proangiogenic, chemokine, cytokine, and coagulation-related factors.
Main Results:
- Pathway analysis identified significant enrichment of proangiogenic factors, chemokines, cytokines, and coagulation-related molecules in pre-PML patients.
- Matrix metalloproteinase 9 (MMP9) was the only validated biomarker.
- Pre-PML patients exhibited significantly reduced MMP9 protein levels at baseline and throughout NTZ treatment compared to NTZ-ctr patients.
Conclusions:
- The proangiogenic factor MMP9 may serve as a potential predictive biomarker for PML development in MS patients receiving NTZ.
- Reduced MMP9 levels at baseline could indicate an increased susceptibility to PML in this patient population.
