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Multiple Sclerosis: From Molecular Pathology to Novel Therapeutic Approaches
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Multiple Sclerosis: From Molecular Pathology to Novel Therapeutic Approaches

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 20 August 2026 | Viewed by 11701

Special Issue Editors

Prof. Dr. László Vécsei

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Guest Editor
1. Department of Neurology, Albert Szent-Györgyi Health Centre, University of Szeged, H-6720 Szeged, Hungary
2. HUN-REN-SZTE Neuroscience Research Group, University of Szeged, H-6720 Szeged, Hungary
Interests: multiple sclerosis; neurodegeneration; smouldering lesion; molecular pathology; novel therapies; kynurenines
Special Issues, Collections and Topics in MDPI journals
Dr. Masaru Tanaka

E-Mail Website
Guest Editor
Danube Neuroscience Research Laboratory, HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged (HUN-REN-SZTE), Tisza Lajos krt. 113, H-6725 Szeged, Hungary
Interests: depression; anxiety; dementia pain; and their comorbidities nature; and translational research in neurological diseases and psychiatric disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Multiple sclerosis (MS) is a chronic disease characterised by inflammation, extensive primary demyelination, and progressive neurodegenerative processes. Long-term disability in MS is largely independent of relapses (progression independent of relapse activity, PIRA) and correlates well with brain atrophy detected by MRI images. Smouldering lesions show a low-grade chronic inflammation characterised by chronic axonal damage and concurrent demyelination and are further characterised by a gradual increase in size towards the normal-appearing white matter (NAWM). During the course of the disease, the proportion of smouldering lesions increases over time and is higher in progressive than in relapsing–remitting disease. These lesions have also been shown to correlate with disability and predict progression in both relapsing–remitting and secondary progressive SM. It is important to revise the current disease classification system, clinical trial designs, and trial endpoints. Furthermore, novel molecular biomarkers (like NfL, GFAP, CHI3L, CXCL13, kynurenines, redox molecules, etc.) help the decision about the optimal treatment of MS patients.

Prof. Dr. László Vécsei
Dr. Masaru Tanaka
Guest Editors

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Keywords

  • progression-independent relapses (PIRAs)
  • smouldering-associated worsening (SAW)
  • lack of new relapses and of new magnetic resonance imaging activity (NEIDA)
  • slowly expanding lesions (SEL)
  • no evidence of smouldering disease activity (NESDA)
  • neurofilament (NfL)
  • glial fibrillary acidic protein (GFAP)
  • patient-reported outcome (PRO)
  • paramagnetic rim lesions (PRLs)
  • relapse-associated worsening (RAW)

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Published Papers (6 papers)

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Research

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13 pages, 936 KB  
Article
Diroximel Fumarate-Loaded Solid Lipid Nanoparticles (DRF-SLNs) as Potential Carriers for the Treatment of Multiple Sclerosis: Preformulation Study
by Debora Santonocito, Giuliana Greco, Maria Grazia Sarpietro, Aurélie Schoubben, Claudia Sciacca, Giuseppe Romeo, Katia Mangano and Carmelo Puglia
Int. J. Mol. Sci. 2025, 26(24), 11827; https://doi.org/10.3390/ijms262411827 - 7 Dec 2025
Viewed by 497
Abstract
Diroximel fumarate (DRF) is an orally administered prodrug used in multiple sclerosis (MS) treatment. Although it exhibits better gastrointestinal (GI) tolerability than its analogues, many patients still discontinue therapy due to frequent GI adverse events. To overcome these limitations, alternative drug delivery systems [...] Read more.
Diroximel fumarate (DRF) is an orally administered prodrug used in multiple sclerosis (MS) treatment. Although it exhibits better gastrointestinal (GI) tolerability than its analogues, many patients still discontinue therapy due to frequent GI adverse events. To overcome these limitations, alternative drug delivery systems that bypass the GI tract are needed. Direct nose-to-brain delivery represents a promising approach to circumvent the blood–brain barrier and target the central nervous system; however, limited nasal mucosal absorption and the small volume of the nasal cavity pose significant challenges. Solid lipid nanoparticles (SLNs) can potentially overcome these obstacles by enhancing drug bioavailability and protecting against enzymatic degradation. This research aimed to develop an innovative intranasal nanoformulation of DRF to improve brain targeting and patient compliance. DRF-loaded SLNs were prepared using a solvent-diffusion technique with stearic acid as the lipid phase and Poloxamer 188 as the surfactant. The obtained nanoparticles displayed favorable technological characteristics, with a mean diameter of 210 nm, a polydispersity index of 0.17, and a zeta potential of −36 mV, suggesting good long-term stability. Interactions between SLNs and biomembrane models (MLV) were also studied to elucidate their cellular uptake mechanism. Future work will focus on evaluating the in vivo efficacy of this novel nanoformulation. Full article
(This article belongs to the Special Issue Multiple Sclerosis: From Molecular Pathology to Novel Therapeutic Approaches)
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14 pages, 675 KB  
Article
Assessing Peripheral Blood Biomarkers and Predictive Patterns in Multiple Sclerosis Using Cytokines and Immune Gene Expression Profiles in Ocrelizumab-Treated Patients: Tracking Tumor Necrosis Factor
by Bojan Jevtić, Nikola Momcilovic, Goran Stegnjaić, Milica Lazarević, Suzana Stanisavljević, Olivera Tamas, Nikola Veselinovic, Maja Budimkic, Sarlota Mesaros, Đorđe Miljković, Tatjana Pekmezovic, Jelena Drulovic and Neda Nikolovski
Int. J. Mol. Sci. 2025, 26(23), 11295; https://doi.org/10.3390/ijms262311295 - 22 Nov 2025
Viewed by 655
Abstract
Ocrelizumab, a humanized monoclonal anti-CD20 and B cell-depleting antibody, is a disease-modifying therapy for multiple sclerosis (MS), a chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. However, reliable predictive biomarkers of ocrelizumab’s effectiveness, such as cytokine expression profiles in peripheral [...] Read more.
Ocrelizumab, a humanized monoclonal anti-CD20 and B cell-depleting antibody, is a disease-modifying therapy for multiple sclerosis (MS), a chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. However, reliable predictive biomarkers of ocrelizumab’s effectiveness, such as cytokine expression profiles in peripheral blood mononuclear cells (PBMCs), are lacking. The aim of this study was to identify immunological biomarkers of ocrelizumab treatment response in MS patients, during a two-year follow-up. mRNA expression for specific immune molecules in PBMCs was measured, and consequently correlated with the clinical and radiological parameters of disease activity. PBMCs were obtained from 80 MS patients (35 with relapsing–remitting MS-RRMS and 45 with primary progressive-PPMS), immediately before initiating ocrelizumab treatment and thereafter every 6 months (before the administration of the next dose of ocrelizumab). Expression of the B cell marker CD19; the pro-inflammatory cytokines interleukin (IL)1B, IL6, and tumor necrosis factor (TNF); and a costimulatory cell marker CD86 were determined. In both RMS and PPMS patients treated with ocrelizumab, higher baseline expression of TNF was statistically significantly associated with an increased risk of developing evidence of disease activity and a greater likelihood of disability progression, at month 24. This result implies that PBMCs’ TNF mRNA expression might be potentially considered as a prognostic biomarker of ocrelizumab effectiveness in MS patients. However, further studies comprising large cohorts and additional immunological parameters are warranted. Full article
(This article belongs to the Special Issue Multiple Sclerosis: From Molecular Pathology to Novel Therapeutic Approaches)
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12 pages, 984 KB  
Communication
Evaluation of Selected Serum Adipocytokines in Patients with Relapsing–Remitting Multiple Sclerosis Treated with Immunomodulatory Second-Line Drugs
by Bożena Adamczyk, Natalia Morawiec, Robert Kwinta, Michał Rakoca, Sławomir Wawrzyniak, Jolanta Zalejska-Fiolka, Agata Sowa, Ksawier Sawa and Monika Adamczyk-Sowa
Int. J. Mol. Sci. 2025, 26(16), 8070; https://doi.org/10.3390/ijms26168070 - 21 Aug 2025
Cited by 2 | Viewed by 1252
Abstract
Adipocytokines are involved in the pathogenesis of multiple sclerosis by modulating inflammation, blood–brain barrier function and immune responses, which may affect disease course and treatment outcomes. Our study assessed serum levels of visfatin, adiponectin and resistin in patients with relapsing–remitting multiple sclerosis treated [...] Read more.
Adipocytokines are involved in the pathogenesis of multiple sclerosis by modulating inflammation, blood–brain barrier function and immune responses, which may affect disease course and treatment outcomes. Our study assessed serum levels of visfatin, adiponectin and resistin in patients with relapsing–remitting multiple sclerosis treated with fingolimod or natalizumab. We examined 49 patients with relapsing–remitting multiple sclerosis and 38 healthy controls. Participants were divided into three groups: patients treated with fingolimod, those treated with natalizumab and the controls. Serum levels of visfatin, adiponectin and resistin were measured. We analyzed correlations with disease duration, treatment duration and body mass index. Adiponectin levels were significantly higher in patients treated with natalizumab compared to those receiving fingolimod and healthy controls (p < 0.05). In the fingolimod group, visfatin levels increased with treatment duration. The mean level was 51.27 pg/mL for treatment shorter than eighteen months and 59.12 pg/mL for longer treatment (p < 0.05). In the same group, resistin levels correlated positively with body mass index (p < 0.05), while visfatin levels showed a negative correlation (p < 0.05). Fingolimod may affect adipocytokine levels, which could support patient monitoring. Increased adiponectin in natalizumab-treated patients suggests its possible role in the therapeutic mechanism of the treatment. Full article
(This article belongs to the Special Issue Multiple Sclerosis: From Molecular Pathology to Novel Therapeutic Approaches)
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Review

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23 pages, 741 KB  
Review
Kynurenines and Mitochondrial Disturbances in Multiple Sclerosis
by Daniel Pukoli and László Vécsei
Int. J. Mol. Sci. 2025, 26(11), 5098; https://doi.org/10.3390/ijms26115098 - 26 May 2025
Cited by 7 | Viewed by 2663
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease characterised by inflammation, demyelination, and neurodegeneration within the central nervous system. The pathogenesis of MS involves an immune-mediated attack on myelin and neurons, accompanied by blood–brain barrier dysfunction and chronic CNS inflammation. Central to MS [...] Read more.
Multiple sclerosis (MS) is a chronic autoimmune disease characterised by inflammation, demyelination, and neurodegeneration within the central nervous system. The pathogenesis of MS involves an immune-mediated attack on myelin and neurons, accompanied by blood–brain barrier dysfunction and chronic CNS inflammation. Central to MS pathology is dysregulation of the kynurenine pathway, which metabolises tryptophan into neuroactive compounds. Kynurenine pathway (KP) activation, driven by inflammatory cytokines, leads to the production of both neuroprotective (e.g., kynurenic acid, KYNA) and neurotoxic (e.g., quinolinic acid, QUIN) metabolites. Imbalance between these metabolites, particularly increased QUIN production, exacerbates glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunction, contributing to neuronal and oligodendrocyte damage. Mitochondrial dysfunction plays a critical role in the pathophysiology of MS, exacerbating neurodegeneration through impaired energy metabolism and oxidative stress. This review integrates the current understanding of KP dysregulation in multiple sclerosis across disease stages. In RRMS, heightened KP activity correlates with inflammation and neuroprotection attempts through increased KYNA production. In contrast, SPMS and PPMS are associated with a shift towards a more neurotoxic KP profile, marked by elevated QUIN levels and reduced KYNA, exacerbating neurodegeneration and disability progression. Understanding these mechanisms offers insights into potential biomarkers and therapeutic targets for MS, emphasising the need for strategies to rebalance KP metabolism and mitigate neurotoxicity in progressive disease stages. Full article
(This article belongs to the Special Issue Multiple Sclerosis: From Molecular Pathology to Novel Therapeutic Approaches)
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21 pages, 616 KB  
Review
Biomarkers of Progression Independent of Relapse Activity—Can We Actually Measure It Yet?
by Gabriel Bsteh, Assunta Dal-Bianco, Nik Krajnc and Thomas Berger
Int. J. Mol. Sci. 2025, 26(10), 4704; https://doi.org/10.3390/ijms26104704 - 14 May 2025
Cited by 4 | Viewed by 4154
Abstract
Progression independent of relapse activity (PIRA) is increasingly recognized as a key driver of disability in multiple sclerosis (MS). However, the concept of PIRA remains elusive, with uncertainty surrounding its definition, underlying mechanisms, and methods of quantification. This review examines the current landscape [...] Read more.
Progression independent of relapse activity (PIRA) is increasingly recognized as a key driver of disability in multiple sclerosis (MS). However, the concept of PIRA remains elusive, with uncertainty surrounding its definition, underlying mechanisms, and methods of quantification. This review examines the current landscape of biomarkers used to predict and measure PIRA, focusing on clinical, imaging, and body fluid biomarkers. Clinical disability scores such as the Expanded Disability Status Scale (EDSS) are widely used, but may lack sensitivity in capturing subtle relapse-independent progression. Imaging biomarkers, including MRI-derived metrics (brain and spinal cord volume loss, chronic active lesions) and optical coherence tomography (OCT) parameters (retinal nerve fiber layer and ganglion cell-inner plexiform layer thinning), offer valuable insights, but often reflect both inflammatory and neurodegenerative processes. Body fluid biomarkers, such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), are promising indicators of axonal damage and glial activation, but their specificity for PIRA remains limited. This review emphasizes the distinction between predicting PIRA—identifying individuals at risk of future progression—and measuring ongoing PIRA-related disability in real time. We highlight the limitations of current biomarkers in differentiating PIRA from relapse-associated activity and call for a clearer conceptual framework to guide future research. Advancing the precision and utility of PIRA biomarkers will require multimodal approaches, longitudinal studies, and standardized protocols to enable their clinical integration and to improve personalized MS management. Full article
(This article belongs to the Special Issue Multiple Sclerosis: From Molecular Pathology to Novel Therapeutic Approaches)
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17 pages, 1145 KB  
Review
Exosomal microRNAs as Early Transition Biomarkers from Recurrent-Remissive to Secondary Progressive Multiple Sclerosis
by Oana Mosora, Smaranda Maier, Doina Manu, Laura Bărcuțean, Medeea Roman, Mihai Dumitreasă and Rodica Bălașa
Int. J. Mol. Sci. 2025, 26(8), 3889; https://doi.org/10.3390/ijms26083889 - 20 Apr 2025
Cited by 7 | Viewed by 1397
Abstract
Multiple sclerosis (MS) is a chronic, immune-mediated disease that affects young adults, leading to neurological disability. Regardless of the studies and the research involved in developing an efficient disease-modifying therapy (DMT), relapsing-remitting multiple sclerosis (RRMS) will transition to a progressive multiple sclerosis phenotype. [...] Read more.
Multiple sclerosis (MS) is a chronic, immune-mediated disease that affects young adults, leading to neurological disability. Regardless of the studies and the research involved in developing an efficient disease-modifying therapy (DMT), relapsing-remitting multiple sclerosis (RRMS) will transition to a progressive multiple sclerosis phenotype. The moment of transition from RRMS to secondary progressive multiple sclerosis (SPMS) is difficult to predict, and the diagnosis is based on the accumulation of disabilities in the evolution of the disease. Research on microRNAs’ (miRNAs) role in MS began in the early 2000s, with miR-155 frequently cited for its link to blood–brain barrier dysfunction and neurodegeneration, making it an early transition biomarker from RRMS to SPMS. The purpose of this review is to reveal the importance of finding a biomarker from the molecular field that will be able to identify the transition phase so patients can receive high-efficacy treatments and to cease the clinical progression. Full article
(This article belongs to the Special Issue Multiple Sclerosis: From Molecular Pathology to Novel Therapeutic Approaches)
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