Extracellular Vesicle-Derived MicroRNAs as a Biomarker for Therapeutic Response in Multiple Sclerosis

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BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) is the leading cause of neurologic disability in young adults worldwide. Despite the development of 20 disease-modifying treatments (DMTs) aimed at reducing disability, approximately 30% of patients experience therapeutic failure. Identifying early biomarkers for therapeutic response is, therefore, essential to enhance the rate of therapeutic effectiveness. As such, this study aims to investigate the role of circulating extracellular vesicles (EVs) as early biomarkers for clinical parameters associated with treatment response in patients with MS. METHODS: ) cells were assessed both before and at 3 months after treatment initiation. Their correlation with therapeutic response over 12 months in patients with MS was also analyzed. The response to treatment was evaluated using the No Evidence of Disease Activity composite (NEDA), which includes clinical relapses, new lesions on MRI, progression of motor and cognitive disability, and brain atrophy. RESULTS: EV subpopulation reflected cognitive impairment. MicroRNA sequencing demonstrated differential expression of miR-28-3p, miR-326, miR-98-5p, miR-144-5p, miR-98-3p, miR-23a-3p, and miR-146a-5p in responders and non responders. miR-186-5p expression correlated negatively with brain atrophy. Combining EV levels and microRNA expression provided an early and robust model for therapeutic response, with significant correlations enhancing the model's accuracy. DISCUSSION: This study underscores the potential of specific EV characteristics and microRNA content as early biomarkers for treatment response in patients with MS. The downregulation of specific microRNAs emerges as a promising indicator of favorable clinical outcomes, thereby suggesting their utility in early therapeutic decision making. Notably, our findings regarding miR-186-5p as a biomarker for brain atrophy represent a novel contribution to the field. Overall, early EV levels and microRNA content analysis at 3 months after treatment initiation seem to be promising as regards anticipating irreversible neurologic damage, thereby offering a valuable tool for optimizing MS treatment management.

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