Multiple Sclerosis Therapy Research Articles

Multiple Sclerosis and Subcutaneous Panniculitis-like T Cell Lymphoma with Hemophagocytic Syndrome: The Role of Treatment Sequencing in the Pathogenetic Mechanism

Introduction: Although panniculitis-like T cell lymphoma (SPTCL) and hemophagocytic syndrome (HSP) have been described as complications following immunosuppressive treatments, there are no reported cases of concomitant SPTCL/HSP and multiple sclerosis (MS). Materials and Methods: We describe the case of a patient affected by an aggressive phenotype of relapsing remitting MS, characterized by consecutive severe relapses with no complete remission. He developed panniculitis-like T cell lymphoma (SPTCL) and hemophagocytic syndrome (HSP) after receiving multiple immunosuppressive treatments in sequence. Despite the aggressive nature of these complications, the patient responded well to a combination of Gemcitabine and Cisplatin. Discussion and Conclusions: With this case, we suggest that physicians always consider blood diseases as possible MS therapy complications, especially in the sequencing setting, and also consider uncommon treatments in those with autoimmune predispositions.

Risk of cancer development associated with disease-modifying therapies for multiple sclerosis: study protocol for a systematic review and meta-analysis of randomised and non-randomised studies

BackgroundThe association between cancer and multiple sclerosis has long been investigated. Several studies and reviews have examined the risk of cancer among patients with multiple sclerosis treated with disease-modifying therapies (DMTs) but with conflicting results. This study will aim to investigate the association between DMTs for multiple sclerosis and subsequent cancer risk using research synthesis methods.Methods/designWe designed and registered a study protocol for a systematic review and meta-analysis. We will include randomised and non-randomised trials, prospective or retrospective cohort studies, and case–control studies of treatment with DMTs compared with placebo, no treatment, or another active agent. The primary outcome will be the risk of cancer (all-malignant neoplasms) in association with the exposure of DMTs. Secondary outcomes will include site-specific cancers (e.g. breast cancer). Literature searches will be conducted in multiple electronic databases (from their inception onwards), including the following: PubMed/MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). Two researchers will screen all citations, full-text articles, and abstract data independently. The risk of bias (quality) of individual studies will be appraised using an appropriate tool. If feasible, we will use a two-stage approach to evidence synthesis: (1) Peto’s method for meta-analysis of data from randomised trials alone; and (2) Random-effects model for meta-analysis adding data from non-randomised studies. We will calculate odds ratios and their associated 95% confidence intervals. Potential sources of heterogeneity will be explored in additional analyses (e.g. subgroups considering different DMTs individually, mechanism of action, type of control, length of follow-up, mode of treatment).DiscussionThis systematic review and meta-analysis of randomised and non-randomised studies will provide an updated synthesis of the risk of cancer associated with DMTs for adult patients with multiple sclerosis. This study will also examine some factors that may explain potential variations across studies. The findings will be published in a peer-reviewed journal.Systematic review registrationOpen Science Framework (https://osf.io/v4sez).

Higher effect sizes for the detection of accelerated brain volume loss and disability progression in multiple sclerosis using deep-learning

PurposeClinical validation of “BrainLossNet”, a deep learning-based method for fast and robust estimation of brain volume loss (BVL) from longitudinal T1-weighted MRI, for the detection of accelerated BVL in multiple sclerosis (MS) and for the discrimination between MS patients with versus without disability progression. Materials and MethodsA longitudinal normative database of healthy controls (n=563), two mono-scanner MS cohorts (n=414, 156) and a mixed-scanner cohort acquired for various indications (n=216) were included retrospectively. Mean observation period from the baseline (BL) to the last follow-up (FU) MRI scan was 2-3 years. Expanded Disability Status Scale (EDSS) at BL and FU was available in 149 MS patients. Annual BVL was computed using BrainLossNet and Siena and then adjusted for age. Repeated-measures ANOVA and Cohen’s effect size were used to compare BrainLossNet and Siena regarding the detection of accelerated BVL and the differentiation between MS patients with versus without EDSS progression. ResultsCohen’s effect size for the differentiation of patients from healthy controls based on the age-adjusted annual BVL was larger with BrainLossNet than with Siena (MS cohort 1: 0.927 versus 0.495, MS cohort 2: 0.671 versus 0.456, mixed-scanner cohort: 0.918 versus 0.730, all p<0.001). Cohen’s effect size for the discrimination between MS patients with (n=51) versus without (n=98) EDSS progression was larger with BrainLossNet (0.503 versus 0.400, p=0.048). ConclusionBrainLossNet can provide added value in clinical routine and MS therapy trials regarding the detection of accelerated BVL in MS and the differentiation between MS patients with versus without disability progression.

Relapse-Associated and Relapse-Independent Contribution to Overall Expanded Disability Status Scale Progression in Multiple Sclerosis Patients Diagnosed in Different Eras.

The introduction of disease-modifying therapies for multiple sclerosis (MS) has led to a deceleration of disease course over the years. Although decreased relapse rate constitutes a factor, the role of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) in MS course deceleration is still unclear. We retrospectively examined long-term Expanded Disability Status Scale (EDSS) progression in patients referred to the MS Center of Montichiari (Italy) and diagnosed with relapsing-remitting MS from 1980 to 2022. To isolate PIRA, we deducted all EDSS changes associated with relapses from overall EDSS change. We compared the relative contribution of PIRA and RAW to EDSS progression in patients diagnosed in different periods using mixed-effects models. A total of 1,405 patients were included in the study, of whom 231 were diagnosed in 1980-1996 (pre-treatment era), 577 in 1997-2008 (injectable disease-modifying therapy era), and 597 after 2008 (oral drugs, monoclonal antibodies, and anti-CD20 era). Across ages, both PIRA and RAW were reduced in patients diagnosed in more recent periods as compared with earlier periods. The average contribution of PIRA to overall EDSS progression was already predominant in patients diagnosed in 1980-1996 (78%) and in 1997-2008 (76%), but it was significantly increased (p = 0.0009) in patients diagnosed in later years (87%). The deceleration of MS course observed throughout the years is determined not only by fewer RAW events, but also by a reduction in PIRA. However, the shift toward a mostly relapse-independent progression highlights the importance of evaluating new therapies based on their effect on PIRA. ANN NEUROL 2024.

Coeliac disease as a model for understanding multiple sclerosis.

The genetic architecture of multiple sclerosis (MS) is similar to that of coeliac disease, with human leukocyte antigen (HLA) being the greatest genetic determinant in both diseases. Furthermore, similar to the involvement of gluten in coeliac disease, Epstein-Barr virus (EBV) infection is now widely considered to be an important environmental factor in MS. The molecular basis for the HLA association in coeliac disease is well defined, and B cells have a clear role in antigen presentation to gluten-specific CD4+ T cells. By contrast, the mechanisms underlying the HLA association of MS are unknown but accumulating evidence indicates a similar role of B cells acting as antigen-presenting cells. The growing parallels suggest that much could be learned about the mechanisms of MS by using coeliac disease as a model. In this Perspective article, we discuss the insights that could be gained from these parallels and consider the possibility of antiviral treatment against EBV as a therapy for MS that is analogous to the gluten-free diet in coeliac disease.

Age-Related Features of Clinical and Neurological Characteristics and Pathogenetic Therapy in Patients with Multiple Sclerosis

INTRODUCTION: Multiple sclerosis (MS) is a neurological demyelinating disease of the central nervous system manifested by pronounced heterogeneous symptoms. Peculiarities of the onset, progression rate, and severity of syndromes are different in different age groups. An increase in the frequency of exacerbations, high degree of disability of patients in different age groups evidence insufficient effectiveness of the conducted pathogenetic therapy. Due to a wide choice of multiple sclerosis disease modifying drugs (MSDMDs), it is important to study the clinical and neurological characteristics of patients with MS in different age groups with the aim of further developing an individual approach to treatment. AIM: To study clinical and neurological features and effectiveness of pathogenetic therapy of MS in patients of different age groups. MATERIALS AND METHODS: A prospective analysis of the data of neurological examination and results of magnetic resonance imaging of 100 patients of different age groups with relapsing-remitting MS, who received outpatient treatment in Kursk Regional Multidisciplinary Clinical Hospital, was conducted in the period of stable remission. RESULTS: The leading syndromes in patients with relapsing-remitting course of MS were cerebellar (78%) and pyramidal (70%) syndromes, besides, dysfunction of the cranial nerves (71%) was also observed. A quantitative parameter of explicitness of pelvic disorder syndrome predominated in middle-aged and elderly patients compared to young ones (p 0.001). Cognitive disorders were more often (14%) recorded in middle-aged and elderly patients (p 0.001). The use of glatiramer acetate permitted to reduce the degree of disability in young subjects (p 0.05); in patients of the middle age group, the most effective was a timely transition from interferon beta to ocrelizumab (p 0.05). The use of first-line MSDMDs (interferon-beta) in elderly patients demonstrated low effectiveness (p 0.05). CONCLUSION: In middle-aged and elderly patients with equal timing of MS onset, the neurological deficit is more expressed than in young ones. First-line pathogenetic therapy, in particular, glatiramer acetate, is more effective in young patients, while patients of middle age are recommended an early transition to second-line MSDMDs.

Enhancing Quality of Life in Multiple Sclerosis Patients Through Coadministration of FDA-Approved Immunomodulators and Melatonin

Objective: The primary goal of this study was to assess the binding characteristics and affinities of melatonin and certain U.S. Food and Drug Administration (FDA)-approved lipophilic drugs used in the treatment of multiple sclerosis (MS) with the brain and muscle Arnt-like 1 (BMAL1) clock protein. Additionally, the study aimed to investigate their potential as modulators of BMAL1 activity for therapeutic applications in MS.Methods: Molecular docking and simulation studies were conducted to investigate the interactions between the BMAL1 protein and the selected agents as ligands. Docking simulations were performed using AutoDock Vina, and key interactions were analyzed with Biovia Discovery Studio Visualizer. A molecular dynamics simulation was conducted using GROMACS 2020.4 and the binding free energies were calculated using the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method. The pharmacokinetic properties of the ligands were predicted using the BOILED-Egg model implemented in the SwissADME web tool.Results: Melatonin demonstrated the highest binding affinity (-8.5 kcal/mol) and most favorable binding free energy (-245.26±1.27 kJ/mol) with BMAL1, suggesting its potential synergistic activity with other FDA-approved drugs in MS therapy. The pharmacokinetic analysis indicated that all three ligands were likely to cross the blood-brain barrier and exhibit high gastrointestinal absorption, with teriflunomide and melatonin potentially achieving a better profile.Conclusion: This study highlights the potential of concomitant use of melatonin to modulate BMAL1 activity, providing a foundation for developing targeted chronotherapeutic strategies in MS treatment.

Topical review: Lactation and use of DMTs in women with MS.

One in three females with multiple sclerosis (MS) becomes pregnant after diagnosis. In the postpartum period, there is a risk of rebound inflammatory activity. This risk can likely be reduced with breastfeeding, as well as with early initiation of effective therapies that have low therapeutic lag. To guide patients in their choices surrounding breastfeeding and MS therapies, clinicians must be familiar with how best to protect against relapses, to ensure infant safety, and to support breastfeeding choices. This topical review provides a broad framework on lactation in women with MS. It seeks to reframe guidelines around caring for the maternal-infant dyad, and for diverse populations living with MS. It also provides updated data on the effects of lactation in women with MS and the limited data on transfer of disease-modifying therapies (DMTs) into breastmilk. The ultimate goal is to support informed shared decision-making between clinicians and patients regarding breastfeeding during the high-risk postpartum period.

MGlu4R, mGlu7R, and mGlu8R allosteric modulation for treating acute and chronic neurodegenerative disorders.

Neuroprotection, defined as safeguarding neurons from damage and death by inhibiting diverse pathological mechanisms, continues to be a promising approach for managing a range of central nervous system (CNS) disorders, including acute conditions such as ischemic stroke and traumatic brain injury (TBI) and chronic neurodegenerative diseases like Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis (MS). These pathophysiological conditions involve excessive glutamatergic (Glu) transmission activity, which can lead to excitotoxicity. Inhibiting this excessive Glu transmission has been proposed as a potential therapeutic strategy for treating the CNS disorders mentioned. In particular, ligands of G protein-coupled receptors (GPCRs), including metabotropic glutamatergic receptors (mGluRs), have been recognized as promising options for inhibiting excessive Glu transmission. This review discusses the complex interactions of mGlu receptors with their subtypes, including the formation of homo- and heterodimers, which may vary in function and pharmacology depending on their protomer composition. Understanding these intricate details of mGlu receptor structure and function enhances researchers' ability to develop targeted pharmacological interventions, potentially offering new therapeutic avenues for neurological and psychiatric disorders. This review also summarizes the current knowledge of the neuroprotective potential of ligands targeting group III mGluRs in preclinical cellular (in vitro) and animal (in vivo) models of ischemic stroke, TBI, PD, AD, and MS. In recent years, experiments have shown that compounds, especially those activating mGlu4 or mGlu7 receptors, exhibit protective effects in experimental ischemia models. The discovery of allosteric ligands for specific mGluR subtypes has led to reports suggesting that group III mGluRs may be promising targets for neuroprotective therapy in PD (mGlu4R), TBI (mGlu7R), and MS (mGlu8R).

SIRT6 modulates lesion microenvironment in LPC induced demyelination by targeting astrocytic CHI3L1

Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitor or activator, we found that SIRT6 modulated LPC-induced damage in motor or cognitive function. Inhibition of SIRT6 impaired myelin regeneration, exacerbated neurological deficits, and decreased oligodendrocyte precursor cells (OPCs) proliferation and differentiation, whereas activation of SIRT6 reversed behavioral performance in mice, demonstrating a beneficial effect of SIRT6. Importantly, based on RNA sequencing analysis of the corpus callosum tissues, it was further revealed that SIRT6 took charge in regulation of glial activation during remyelination, and significant alterations in CHI3L1 were obtained, a glycoprotein specifically secreted by astrocytes. Impaired proliferation and differentiation of OPCs could be induced in vitro using supernatants from reactive astrocyte, especially when SIRT6 was inhibited. Mechanistically, SIRT6 regulates the secretion of CHI3L1 from reactive astrocytes by histone-H3-lysine-9 acetylation (H3K9Ac). Adeno-associated virus-overexpression of SIRT6 (AAV-SIRT6-OE) in astrocytes improved remyelination and functional recovery after LPC-induced demyelination, whereas together with AAV-CHI3L1-OE inhibits this therapeutic effect. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy.

Challenges in Diagnosis of COVID-19 Pneumonia under Ocrelizumab and De-Risking Strategies in Multiple Sclerosis—The Elephant Is (Still) in the Room

Severe SARS-CoV-2 infections may still be observed in people bearing risk factors, such as the use of anti-CD20 monoclonal antibodies (mAbs), which are adopted in several autoimmune disorders including multiple sclerosis (MS). COVID-19 diagnosis is routinely based on nasopharyngeal swab testing, but suboptimal sensitivity for SARS-CoV-2 detection compared to bronchoalveolar lavage (BAL) may lead to misdiagnosis in some cases. Such diagnostic issues were described in a few MS patients receiving anti-CD20 mAbs, including middle-aged people and lacking information on subsequent MS therapeutic management, a debated topic as no evidence-based guidance on de-risking strategies is currently available. Here, we report the case of a young MS patient who developed severe COVID-19 pneumonia under treatment with the anti-CD20 mAb ocrelizumab, and who was finally diagnosed with SARS-CoV-2 by BAL despite repeatedly negative nasopharyngeal swabs. Ocrelizumab was then discontinued, and treatment with a sphingosine-1 phosphate receptor modulator was started, followed by maintenance of clinical and radiological MS stability. Challenges in diagnosing COVID-19 pneumonia in people without risk factors other than immunomodulatory treatment are hence discussed, as well as potential strategies for de-risking MS therapies. The latter topic is increasingly debated based on raising concerns for potential long-term safety issues of high-efficacy treatments, including anti-CD20 mAbs.

The Role of Mesenchymal Stem Cells in Modulating Adaptive Immune Responses in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, leading to significant disability through neurodegeneration. Despite advances in the understanding of MS pathophysiology, effective treatments remain limited. Mesenchymal stem cells (MSCs) have gained attention as a potential therapeutic option due to their immunomodulatory and regenerative properties. This review examines MS pathogenesis, emphasizing the role of immune cells, particularly T cells, in disease progression, and explores MSCs' therapeutic potential. Although preclinical studies in animal models show MSC efficacy, challenges such as donor variability, culture conditions, migratory capacity, and immunological compatibility hinder widespread clinical adoption. Strategies like genetic modification, optimized delivery methods, and advanced manufacturing are critical to overcoming these obstacles. Further research is needed to validate MSCs' clinical application in MS therapy.

A Real-World Experience of Rituximab: A Panacea in Therapy of Multiple Sclerosis in Low- and Middle-Income Setting.

Anti-CD20 monoclonal antibodies have received increasing attention in the past few years in the treatment of multiple sclerosis (MS). This study describes the (i) efficacy and safety of rituximab in people living with MS and (ii) assesses clinical and imaging outcomes following rituximab in MS. This is a chart review from the MS registry maintained at the institute from a University Hospital in South India. Eighty-three (M:F, 26:57) people living with MS received rituximab as immunomodulation between 2007 and 2022 with a median follow-up duration of 18 months. Fifty-nine (71%) were classified as relapsing-remitting MS, 16 (19%) were secondary progressive MS, and 8 (10%) were primary progressive MS. Seventy-two (87%) MS patients did not experience any relapse after receiving rituximab. In relapsing-remitting MS patients, the mean annualized recurrence rate dropped from 1.24 ± 1.19 to 0.16 ± 0.37. Infusion-related reaction occurred in 5 (6% of adverse events), urinary infections in 7 (8.4%), systemic infections in 3 (3%), Pneumocystis carinii pneumonia occurred in 1 (1%), and herpes zoster infection in 1 (1%) patient. Mortality was observed in 3 (3.5%) patients. While being on rituximab, 18 (22%) patients had mild COVID-19 illness and they all made complete recovery without any sequalae. Rituximab is a safe, well-tolerated, easily accessible, inexpensive, and effective therapeutic option for people with MS. Rituximab showed both clinical and radiological improvement after a median follow-up of 1.5 years. None of our patients showed any severe COVID infection nor side effects after receiving COVID vaccination.

Sox2-mediated transdifferentiation of hAT-MSCs into induced neural progenitor-like cells for remyelination therapies

Mesenchymal stem cells (MSCs) are converted to neural cells using growth factors and chemicals. Although these neural cells are effective at modulating disease symptoms, they are less effective at replacing lost neural cells. Direct transdifferentiation seems to be a promising method for generating the required cells for regenerative medicine applications. Sox2 is a key transcription factor in neural progenitor (NP) fate determination and has been frequently used for transdifferentiating different cell types to NPs. Here, we demonstrated that the overexpression of a single transcription factor, Sox2, in human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) led to the generation of induced NPs-like cells that were clonogenic, proliferative and passageable, and showed the potential to differentiate into three neural lineages. NPs are known as progenitors with the potential to differentiate into oligodendrocytes. In vivo, following transplantation into demyelinated adult mouse brains, they survived, differentiated and integrated into the adult brain while participating in the remyelination process and behavioral improvement. This report introduces a beneficial, low-cost and effective approach for generating NPs from an accessible adult source for autologous applications in treating neurodegenerative diseases, including remyelination therapies for multiple sclerosis and other demyelinating diseases.

Patient and Physician Perspectives of Treatment Burden in Multiple Sclerosis.

The number of disease-modifying therapies (DMTs) approved for the treatment of multiple sclerosis (MS) has greatly increased in recent decades, leading to higher treatment complexity. DMTs can differ in mode and frequency of administration, benefit-risk profile, and associated costs. Patients with MS contend not only with the burden of their chronic disease but also with the treatment burden of their MS therapy. Adhering to dosing schedules and infusion appointments can be difficult for busy, working-age patients or those with limited access to transportation. Patients and healthcare professionals (HCPs) may have differing priorities, concerns, and preferences when selecting treatment, potentially affecting treatment satisfaction and, importantly, adherence. Additionally, patients face direct and indirect costs related to treatment. These factors can all contribute to a high treatment burden on patients, impacting their quality of life and potentially leading to worse patient outcomes. HCPs, patients, and caregivers must work together to alleviate treatment burden through effective communication, shared decision-making, appreciating each other's perspectives, and additional HCP support. Consideration of treatment burden into clinical guidelines is also warranted. In this review, we examine key factors impacting treatment burden for patients with MS, with a focus on the patient perspective as provided by our patient authors, and provide strategies to minimize treatment burden.

YOGA CAN AMELIORATE QUALITY OF LIFE OF PATIENTS WITH MULTIPLE SCLEROSIS: A REVIEW

Multiple sclerosis (MS) is a condition in which the body's immune system mistakenly attacks the central nervous system (CNS). MS is characterised by the presence of inflammation, demyelination, and the formation of scar (sclerosis) in the white matter of the brain and spinal cord. This leads to a wide range of symptoms associated with multiple sclerosis, encompassing physical, emotional, and psychological manifestations such as fatigue, chronic pain, impaired mobility, imbalance, spasticity, cognitive impairment, depression, bladder and bowel dysfunction, visual and speech impairments and sensory disturbances. Currently, the aetiology and treatment for MS are still unidentified, and it impacts over 2.8 million individuals globally. Disease modifying therapy (DMT) for MS, which aids in reducing the development of lesions in the white matter of the central nervous system (CNS), is expensive and has notable side effects. Consequently, individuals diagnosed with MS are increasingly turning to complementary and alternative medicine (CAM) as a means to alleviate or conquer MS symptoms and improve their overall quality of life. Among the many kinds of CAM, yoga has emerged as a particularly popular choice. The present review aims to elucidate the possible influence of yoga on enhancing the quality of life in individuals diagnosed with MS. A comprehensive search was undertaken on Google Scholar, included fourteen publications published between 2004 and February 2024. Based on the available data of low to moderate quality, yoga seems to be useful in enhancing the quality of life for individuals with MS.

Association of chronotype and timing of interferon injection with severity of IFNβ-induced flu-like syndrome in Multiple sclerosis (MS) patients

BackgroundAlthough Interferon-beta (IFNβ) has long been approved as a disease-modifying therapy (DMT) for Multiple sclerosis (MS), flu-like syndrome (FLS) persists as a common adverse effect of interferon therapy. Given the importance of circadian rhythm in regulating physiological processes, we aimed to assess the relationship between patient’s chronotype and time of interferon injection with FLS score in MS patients receiving IFNβ. MethodsA cross-sectional study was conducted on 118 MS patients who were referred to the clinic of neurology of Zanjan Vali-e-Asr Hospital for interferon injection. The included were invited to complete a morningness-eveningness questionnaire (MEQ) assessing patients’ chronotype. The following data were extracted from patients’ record: age, gender, duration of interferon treatment, type of interferon taken, time of interferon injection (morning/evening), FLS score, MS subtype, and usage of pain killers. All data found were imported and statistically analyzed in SPSS ver.26. ResultsAccording to the patients’ record, 114 (96.6%) patients had experienced post-interferon injection FLS with different severities. Statistical analysis revealed no significant relationship between the patient’s chronotype and FLS score. Nevertheless, the FLS score was significantly higher in those who had evening injections. ConclusionsTime of interferon injection was significantly associated with FLS score, with higher FLS score following evening injection. However, no significant relationship was found between the FLS score and the patient’s chronotype. It is recommended that further studies assessing circadian rhythm using laboratory tests such as melatonin measurement need to be undertaken to investigate the association of circadian rhythm with post-interferon injection FLS.

Circulating platelets modulate oligodendrocyte progenitor cell differentiation during remyelination

Revealing unknown cues that regulate oligodendrocyte progenitor cell (OPC) function in remyelination is important to optimise the development of regenerative therapies for multiple sclerosis (MS). Platelets are present in chronic non-remyelinated lesions of MS and an increase in circulating platelets has been described in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for MS. However, the contribution of platelets to remyelination remains unexplored. Here we show platelet aggregation in proximity to OPCs in areas of experimental demyelination. Partial depletion of circulating platelets impaired OPC differentiation and remyelination, without altering blood-brain barrier stability and neuroinflammation. Transient exposure to platelets enhanced OPC differentiation in vitro, whereas sustained exposure suppressed this effect. In a mouse model of thrombocytosis (Calr+/-), there was a sustained increase in platelet aggregation together with a reduction of newly-generated oligodendrocytes following toxin-induced demyelination. These findings reveal a complex bimodal contribution of platelet to remyelination and provide insights into remyelination failure in MS.

Circulating platelets modulate oligodendrocyte progenitor cell differentiation during remyelination.

Revealing unknown cues that regulate oligodendrocyte progenitor cell (OPC) function in remyelination is important to optimise the development of regenerative therapies for multiple sclerosis (MS). Platelets are present in chronic non-remyelinated lesions of MS and an increase in circulating platelets has been described in experimental autoimmune encephalomyelitis (EAE) mice, an animal model for MS. However, the contribution of platelets to remyelination remains unexplored. Here we show platelet aggregation in proximity to OPCs in areas of experimental demyelination. Partial depletion of circulating platelets impaired OPC differentiation and remyelination, without altering blood-brain barrier stability and neuroinflammation. Transient exposure to platelets enhanced OPC differentiation in vitro, whereas sustained exposure suppressed this effect. In a mouse model of thrombocytosis (Calr+/-), there was a sustained increase in platelet aggregation together with a reduction of newly-generated oligodendrocytes following toxin-induced demyelination. These findings reveal a complex bimodal contribution of platelet to remyelination and provide insights into remyelination failure in MS.

Parenteral anti-B cell therapy for multiple sclerosis: From origins to the creation of the Russian drug divosilimab

Parenteral anti-B cell therapy for multiple sclerosis: From origins to the creation of the Russian drug divosilimab