Carbone Fortunata, Colamatteo Alessandra, Micillo Teresa, Abbadessa Gianmarco, Garavelli Silvia, Fusco Clorinda, Russo Claudia, Perna Francesco, Garziano Federica, La Rocca Claudia, Mottola Maria, Maniscalco Giorgia Teresa, Bonavita Simona, Spiezia Antonio Luca, Castiello Alessia, Lanzillo Roberta, Brescia Morra Vincenzo, Procaccini Claudio, de Candia Paola, Matarese Giuseppe
Istituto degli Endotipi in Oncologia, Metabolismo e Immunologia, Consiglio Nazionale delle Ricerche (IEOMI-CNR), Napoli, Italy.
Unità di Neuroimmunologia, IRCCS Fondazione Santa Lucia, Roma, Italy.
Ann Clin Transl Neurol. 2025 Aug;12(8):1595-1607. doi: 10.1002/acn3.70093. Epub 2025 Jun 11.
Despite the availability of effective therapies for Multiple Sclerosis (MS), the unpredictable nature of disease progression and the variability in individual treatment outcomes call for reliable biomarkers. This pilot study aims to investigate the potential of plasma circulating microRNAs (miRNAs) as predictive biomarkers for clinical responses to dimethyl fumarate (DMF), a widely used oral treatment for MS.
Peripheral blood samples were collected from nineteen treatment-naïve people with relapsing-remitting MS (pwRRMS) before and after 3, 6, 12, and 24 months of DMF administration, as well as from nineteen healthy individuals. MiRNAs were quantified by RT-qPCR after plasma RNA extraction, and peripheral blood immune cells were analyzed by flow cytometry. Pathway enrichment and protein-protein interaction analyses were performed to identify the biological processes and molecular networks associated with mRNAs targeted by the specific DMF-modulated miRNAs.
We identified a DMF-modulated miRNA signature with significant changes occurring at early treatment stages. Notably, specific miRNAs were correlated with both clinical and immunological outcomes upon DMF treatment, including lymphocyte count reduction (let-7b-5p and miR-223-3p) and disease progression over 2 years (miR-223-3p, miR-23a-3p, miR-23b-3p, miR-27a-3p, and miR-27b-3p), suggesting their potential as predictive biomarkers for treatment response. Moreover, the validated mRNA targets of DMF-modulated miRNAs were enriched for IL-6 signaling and NRF2-dependent antioxidant pathways, highlighting the potential molecular mechanisms underpinning DMF efficacy.
This small exploratory study underscores the potential of plasma circulating miRNAs as candidate biomarkers for predicting therapeutic outcomes in MS and it calls for validation in larger studies, which may enhance our understanding of disease pathophysiology and offer a promising tool for personalized treatment strategies.
尽管已有针对多发性硬化症（MS）的有效疗法，但疾病进展的不可预测性以及个体治疗结果的变异性仍需要可靠的生物标志物。这项初步研究旨在调查血浆循环微小RNA（miRNA）作为对富马酸二甲酯（DMF，一种广泛用于治疗MS的口服药物）临床反应的预测生物标志物的潜力。
采集了19例未经治疗的复发缓解型MS患者（pwRRMS）在DMF给药3、6、12和24个月前后的外周血样本，以及19名健康个体的外周血样本。血浆RNA提取后通过RT-qPCR对miRNA进行定量，并通过流式细胞术分析外周血免疫细胞。进行通路富集和蛋白质-蛋白质相互作用分析，以确定与特定DMF调节的miRNA靶向的mRNA相关的生物学过程和分子网络。
我们确定了一个DMF调节的miRNA特征，在治疗早期阶段发生了显著变化。值得注意的是，特定的miRNA与DMF治疗后的临床和免疫结果相关，包括淋巴细胞计数减少（let-7b-5p和miR-223-3p）以及2年内的疾病进展（miR-223-3p、miR-23a-3p、miR-23b-3p、miR-27a-3p和miR-27b-3p），表明它们作为治疗反应预测生物标志物的潜力。此外，DMF调节的miRNA的经过验证的mRNA靶点在IL-6信号通路和NRF2依赖性抗氧化途径中富集，突出了DMF疗效的潜在分子机制。
这项小型探索性研究强调了血浆循环miRNA作为预测MS治疗结果的候选生物标志物的潜力，并呼吁在更大规模的研究中进行验证，这可能会增进我们对疾病病理生理学的理解，并为个性化治疗策略提供一个有前景的工具。
