Treatment Of Multiple Sclerosis Research Articles

Pharmacokinetics and Pharmacodynamics of Natalizumab 6-Week Dosing vs Continued 4-Week Dosing for Relapsing-Remitting Multiple Sclerosis.

Exposure to natalizumab, an efficacious treatment for relapsing-remitting multiple sclerosis (RRMS), is associated with increased risk of progressive multifocal leukoencephalopathy (PML). Compared with every-4-week (Q4W) dosing, extended-interval dosing of natalizumab is associated with decreased risk of PML. Clinical efficacy was maintained in the majority of patients switched to every-6-week (Q6W) dosing in the phase 3b NOVA clinical trial. In this article, we report pharmacokinetics (PK) and pharmacodynamics (PD) of Q6W vs Q4W dosing in NOVA. In NOVA study Part 1, participants with RRMS (aged 18-60 years) and Expanded Disability Status Scale score <5.5, who were stable on IV natalizumab Q4W dosing for ≥12 months, were randomized to continue IV Q4W dosing or switched to IV Q6W dosing of natalizumab and followed for 72 weeks. Exploratory outcomes were measurements of trough serum natalizumab concentration, α4-integrin saturation, and soluble vascular cell adhesion molecule-1 (sVCAM-1) concentration. A mixed model of repeated measures was used to estimate mean treatment differences between groups. Patient-level PK and PD data were examined in those with relapse or radiologic disease activity. In NOVA, 486 (Q6W, n = 245; Q4W, n = 241) and 487 (Q6W, n = 246; Q4W, n = 241) participants were included in the PK and PD populations, respectively. Mean trough natalizumab concentrations ranged from 10 to 21 μg/mL (Q6W) and 33-38 μg/mL (Q4W), and mean α4-integrin saturation remained above 65.5% (Q6W) and above 77.9% (Q4W). In the Q6W group, mean sVCAM-1 levels increased 23.6% by week 24 and remained elevated throughout the study, while mean sVCAM-1 levels remained generally stable in the Q4W group. Most participants with T2 lesion activity or relapse activity, in either treatment arm, maintained trough natalizumab levels >10 μg/mL and trough α4-integrin saturation >50%. Compared with Q4W dosing, Q6W dosing was associated with a 60%-70% decrease in mean trough natalizumab levels and a 9%-16% decrease in mean α4-integrin saturation. At the patient level, neither natalizumab concentration nor α4-integrin saturation was consistently predictive of lesion or relapse activity, suggesting that trough natalizumab and α4-integrin saturation measurements should be interpreted with caution in clinical practice. ClinicalTrials.gov, NCT03689972; EudraCT, 2018-002145-11. Submitted 2018-09-27. First patient enrolled: 2018-12-26. https://clinicaltrials.gov/study/NCT03689972.

Expression of STAT- and T-cell-related genes in women with first-line treatment of relapsing-remitting multiple sclerosis.

Relapsing-remitting multiple sclerosis is associated with changes in Jak/STAT pathways in immune cells, but the influence of disease-modifying drugs on these pathways is poorly understood. The aim of this study was to evaluate the impact of first-line disease-modifying drugs used in treatment of RRMS on expression of the STAT pathway and T-cell-related genes in the blood and on serum concentrations of sgp130 and TGF-β1 in women, as well as on the level of phosphorylated STAT3 and STAT5 proteins in T cells of untreated patients and heathy controls. Expression of STAT1, STAT3, STAT5A, STAT5B, SOCS1, SOCS3, FOXP3, IKZF2, RORC and ICOS genes in the blood of untreated RRMS patients, in the blood of patients treated with interferon-β, glatiramer acetate, dimethyl fumarate or teriflunomide and in the blood of healthy controls was evaluated using droplet digital PCR. Serum concentrations of sgp130 and TGF-β1 were evaluated by ELISA. Phosphorylated STAT3 and STAT5 protein levels in T cells were evaluated by flow cytometry. STAT3 gene expression was significantly higher in untreated patients than in healthy control, but the level of phosphorylated STAT3 in T cells was significantly lower. Patients treated with interferon-β or dimethyl fumarate had significantly lower STAT3 gene expression. Patients treated with teriflunomide had higher STAT1 gene expression, than untreated patients. Patients treated with dimethyl fumarate also had significantly lower RORC gene expression than untreated patients. The study shows the impact of drugs used in first-line treatment of relapsing-remitting multiple sclerosis on expression of STAT and T-cell-related genes.

All roads lead to cholesterol: Modulating lipid biosynthesis in multiple sclerosis patient-derived models

Studies from Ionescu etal.1 and Clayton etal.2 using multiple sclerosis (MS) patient-derived cell models underscore cholesterol metabolism's role in inflammatory and dysfunctional cell phenotypes in the disease. Inhibiting cholesterol biosynthesis ameliorated critical cellular phenotypes, emphasizing the need to further investigate this pathway as a potential target for MS treatment.

The role of disease modifying therapies in late-onset multiple sclerosis: A Portuguese multicentric characterization study

IntroductionKnowledge about the effect of disease modifying treatment (DMT) in late-onset multiple sclerosis (LOMS, onset ≥50 years-old) is scarce. This study aims to evaluate the association between DMT use and multiple sclerosis (MS) evolution in a LOMS cohort. MethodsThis multicentre, retrospective and observational study included LOMS patients with ≥2 years of follow-up. Data on demographics, clinical/paraclinical (baseline and follow-up), DMT and adverse events were collected. Primary outcomes were irreversible EDSS 4.0 and 6.0 achievement and first year ARR. Univariate and multivariate regression models were conducted, with treated and/or relapsing phenotypes (RMS) subgroups analyses. ResultsWe included 232 patients (53.4 % with RRMS phenotype; 84.9 % submitted to DMT; median follow-up time of 141.5 (IQR 92.7–193.1) months). Treatment versus non-treatment did not affect EDSS milestones in multivariate analysis (adjusted to phenotype, baseline EDSS, age, and ARR), but initially receiving monoclonal antibodies (MAbs) was associated with lower odds of EDSS 4.0 (OR 0.13). In treated patients, starting with high efficacy DMT (HE-DMT) was related to a lower chance of EDSS 4.0 (OR 0.05) and 6.0 (OR 0.26) compared with being exclusively treated with moderate efficacy DMT (ME-DMT), with similar results when analysing the subgroup of RMS treated patients. In multivariate models, initial treatment with MAbs (vs. non-treatment) and with HE-DMT (vs. ME-DMT) were related to a lower first year ARR; when considering only RMS patients, every DMT class analysed reduced first year ARR vs. non-treatment. During DMT, we documented a rate of 0.6 % serious infections, 0.07 % opportunistic infections and 0.7 % neoplasm diagnosis per patient year. ConclusionDMT type and therapeutic strategy influenced LOMS disability accumulation and relapses in our cohort. Our findings support the importance of investment in LOMS treatment optimization.

Computational Analysis of S1PR1 SNPs Reveals Drug Binding Modes Relevant to Multiple Sclerosis Treatment

Background/Objectives: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) characterized by myelin and axonal damage with a globally rising incidence. While there is no known cure for MS, various disease-modifying treatments (DMTs) exist, including those targeting Sphingosine-1-Phosphate Receptors (S1PRs), which play important roles in immune response, CNS function, and cardiovascular regulation. This study focuses on understanding how nonsynonymous single nucleotide polymorphisms (rs1299231517, rs1323297044, rs1223284736, rs1202284551, rs1209378712, rs201200746, and rs1461490142) in the S1PR1’s active site affect the binding of endogenous ligands, as well as different drugs used in MS management. Methods: Extensive molecular dynamics simulations and linear interaction energy (LIE) calculations were employed to predict binding affinities and potentially guide future personalized medicinal therapies. The empirical parameters of the LIE method were optimized using the binding free energies calculated from experimentally determined IC50 values. These optimized parameters were then applied to calculate the binding free energies of S1P to mutated S1PR1, which correlated well with experimental values, confirming their validity for assessing the impact of SNPs on S1PR1 binding affinities. Results: The binding free energies varied from the least favorable −8.2 kcal/mol for the wild type with ozanimod to the most favorable −16.7 kcal/mol for the combination of siponimod with the receptor carrying the F2055.42L mutation. Conclusions: We successfully demonstrated the differences in the binding modes, interactions, and affinities of investigated MS drugs in connection with SNPs in the S1PR1 binding site, resulting in several viable options for personalized therapies depending on the present mutations.

Towards Treating Multiple Sclerosis Progression

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). In most patients, the disease starts with an acute onset followed by a remission phase, subsequent relapses and a later transition to steady chronic progression. In a minority of patients, this progressive phase develops from the beginning. MS relapses are characterized predominantly by the de novo formation of an inflammatory CNS lesion and the infiltration of immune cells, whereas the pathological features of MS progression include slowly expanding lesions, global brain atrophy and an inflammatory response predominantly mediated by macrophages/microglia. Importantly, this CNS-intrinsic pathophysiology appears to initiate early during the relapsing–remitting disease phase, while it turns into the key clinical MS feature in later stages. Currently approved disease-modifying treatments for MS are effective in modulating peripheral immunity by dampening immune cell activity or preventing the migration of immune cells into the CNS, resulting in the prevention of relapses; however, they show limited success in halting MS progression. In this manuscript, we first describe the pathological mechanisms of MS and summarize the approved therapeutics for MS progression. We also review the treatment options for progressive MS (PMS) that are currently under investigation. Finally, we discuss potential targets for novel treatment strategies in PMS.

OA08 Ocrelizumab in pregnancy in a patient with juvenile onset systemic lupus erythematosus

Abstract Introduction Juvenile-onset systemic lupus erythematosus (jSLE) is a multisystem autoimmune disease that results in increased disease activity compared to adult-onset SLE. jSLE in pregnancy results in a greater incidence of disease flares as well as adverse pregnancy outcomes. Management of SLE in pregnancy is particularly difficult due to lack of safety data for immunosuppressant medications and is therefore limited. Ocrelizumab is a humanised monoclonal antibody that selectively targets CD20 B cells and is approved for the treatment of multiple sclerosis. Despite never being trialled in a patient with active SLE in pregnancy, this case demonstrates its use with a successful outcome. Case description An 18-year-old female was diagnosed at age 14 with juvenile onset systemic lupus erythematosus with the presence of a photosensitive malar rash, arthralgia, alopecia, aphthous ulcers and headache. At the time of diagnosis her investigations revealed ANA 1:5120 with homogenous pattern, high dsDNA, low C3 and C4, thrombocytopenia, antibodies to Smith, Ro, RNP, anti-Rib-P, strongly positive lupus anticoagulant antibodies and low titre anti-cardiolipin IgG and IgM. Previous treatment included methotrexate, mycophenolate mofetil and cyclosporin which were discontinued either due to patient choice, inefficacy or adverse reaction. Azathioprine was contraindicated due to low TMPT. Rituximab was trialled and although effective had to be stopped due to adverse reaction. Unfortunately, she experienced a primigravida pregnancy loss at 15-20 weeks secondary to active SLE and pre-eclampsia. Shortly after this, she developed a rare case of anti-fascin antibody neuropathy and was treated with ocrelizumab. Six months later during her second pregnancy, she was treated with hydroxychloroquine 400 mg, aspirin 150 mg, folic acid 5 mg and low molecular weight heparin prophylaxis which were continued throughout the pregnancy. Due to concerns of active lupus at 13 weeks due to facial rash and fatigue, prednisolone was commenced at 10 mg daily and continued. After careful consideration, Ocrelizumab was given in the second trimester at 17 and 19 weeks’ gestation. Following this, symptoms remained under control and disease activity was low with normal C3/C4 and dsDNA levels without significant proteinuria. A newborn baby was delivered at 38 weeks by caesarean section without complication or foetal abnormalities. Both the mother and baby remain under close follow- up but have not demonstrated adverse outcomes at 3 months postpartum. Discussion This case demonstrates the use of Ocrelizumab in the second trimester of a high-risk pregnancy complicated by active jSLE. At present, there is no license for use of Ocrelizumab in SLE and no safety data on its use in pregnancy. However, there was a good outcome for this patient which resulted in no antenatal or postpartum complications and the successful birth of a healthy newborn without foetal abnormalities. Ocrelizumab is used for the treatment of early relapsing-remitting multiple sclerosis (RRMS) and is increasingly used by neurologists in women of childbearing age despite being unlicensed for use in pregnancy. Concerns of its use in pregnancy surround B cell depletion in the neonate which while tends to be transient, causes significant concern regarding long term immunological development and response to vaccination. B cell depleting therapies are widely used in the context of active and refractory SLE and therefore use of Ocrelizumab has been evaluated in cases of SLE in two phase III clinical trials. The first study examined the efficacy of Ocrelizumab in SLE without renal involvement (BEGIN) and the second recruited patients with lupus nephritis (BELONG). The BEGIN study was terminated early due to lack of response and the BELONG study was terminated due to a significant increase in serious infections (in the Ocrelizumab plus mycophenolate treatment group). However, results on disease activity were positive with complete renal response being achieved non-statistically more frequently in the Ocrelizumab treated patients versus placebo. Real world evidence shows the importance of achieving disease control in SLE around pregnancy to prevent adverse outcomes. The decision for the use of Ocrelizumab therefore needs to be balanced carefully against potential harm to the baby either from direct foetal exposure to the drug, or from gestation in an immunocompromised mother. Key learning points • Pre-pregnancy counselling is of paramount importance in severe cases of active SLE and when possible, pregnancy should be postponed in these instances until disease activity is stabilised with contraception counselling offered to those on teratogenic immunosuppressive agents. • A multidisciplinary approach to the management of complex SLE in pregnancy in essential with obstetrician, midwife, maternal medicine physician and rheumatologist input. • The benefit of potentially life-saving immunosuppressive treatment should be carefully balanced against the poor outcomes of active SLE in pregnancy and decisions should be made on a case-by-case basis.

Fingolimod, a sphingosine-1-phosphate receptor modulator, prevents neonatal bronchopulmonary dysplasia and subsequent airway remodeling in a murine model.

Neonatal bronchopulmonary dysplasia (BPD) is associated with alveolar simplification and airway remodeling. Airway remodeling leads to deformation of airways characterized by peribronchial collagen deposition and hypertrophy of airway smooth muscle, which contribute to the narrowing of airways. Poorly developed lungs contribute to reduced lung function that deteriorates with the passage of time. We have earlier shown that sphingosine kinase 1 (SPHK 1)/sphingosine-1-phosphate (S1P)/S1P receptor1 (S1PR1) signaling plays a role in the pathogenesis of BPD. In this study, we investigated the role of fingolimod or FTY720, a known S1PR1 modulator approved for the treatment of multiple sclerosis in the treatment of BPD. Fingolimod promotes the degradation of S1PR1 by preventing its recycling, thus serving as the equivalent of an inhibitor. Exposure of neonatal mice to hyperoxia enhanced the expression of S1PR1 in both airways and alveoli as compared with normoxia. This increased expression of S1PR1 in the airways persisted into adulthood, accompanied by airway remodeling and airway hyperreactivity (AHR) after neonatal hyperoxia. Intranasal fingolimod at a much lower dose compared with the intraperitoneal route of administration during neonatal hyperoxia improved alveolarization in neonates and reduced airway remodeling and AHR in adult mice associated with improved lung function. The intranasal route was not associated with the lymphopenia seen with the intraperitoneal route of administration of the drug. An increase in S1PR1 expression in the airways was associated with an increase in the expression of enzyme lysyl oxidase (LOX) in the airways following hyperoxia, which was suppressed by fingolimod. This association warrants further investigation.NEW & NOTEWORTHY The role of the S1P receptor1 modulator, fingolimod, as an FDA-approved drug in preventing the recurrence of multiple sclerosis is established. Fingolimod prevented bronchopulmonary dysplasia (BPD) and its sequela of airway remodeling in a neonatal murine model. This protection was associated with the downregulation of lysyl oxidase signaling pathway. Fingolimod could be repurposed for the therapy of BPD.

Discovery of Anthranilic Acid Derivatives as Antagonists of the Pro-Inflammatory Orphan G Protein-Coupled Receptor GPR17.

The G protein-coupled receptor 17 (GPR17) is an orphan receptor involved in inflammatory diseases. GPR17 antagonists have been proposed for the treatment of multiple sclerosis due to their potential to induce remyelination. Potent, selective antagonists are required to enable target validation. In the present study, we describe the discovery of a novel class of GPR17 antagonists based on an anthranilic acid scaffold. The compounds' potencies were evaluated in calcium mobilization and radioligand binding assays, and structure-activity relationships were analyzed. Selected antagonists were additionally studied in cAMP and G protein activation assays. The most potent antagonists were 5-methoxy-2-(5-(3'-methoxy-[1,1'-biphenyl]-2-yl)furan-2-carboxamido)benzoic acid (52, PSB-22269, Ki 8.91 nM) and its 3'-trifluoromethyl analog (54, PSB-24040, Ki 83.2 nM). Receptor-ligand docking studies revealed that the compounds' binding site is characterized by positively charged arginine residues and a lipophilic pocket. These findings yield valuable insights into this poorly characterized receptor providing a basis for future drug development.

Clinicians' Preferences for Sphingosine-1-Phosphate Receptor Modulators in Multiple Sclerosis Based on Clinical Management Considerations: A Choice Experiment.

Four sphingosine-1-phosphate receptor (S1PR) modulators are currently available in the USA for treating relapsing forms of multiple sclerosis (MS). These S1PR modulators have similar efficacy. Clinicians may therefore consider other factors, such as clinical management considerations, when distinguishing among treatments. This study estimated which S1PR modulator clinicians would choose on the basis of a treatment's clinical management and quantified how individual aspects of clinical management might drive this choice. A multi-criteria decision analysis (MCDA) was conducted on the basis of clinical management preferences elicited in a discrete choice experiment (DCE) and real-world clinical management profiles of the S1PR modulators currently available to treat relapsing forms of MS (fingolimod, ozanimod, ponesimod, siponimod). The DCE was completed by neurologists in the USA experienced in treating MS and included eight clinical management attributes: first-dose observations, genotyping, liver function tests, eye exams, drug-drug interactions, interactions with antidepressants, interactions with foods high in tyramine, and immune system recovery time. Attribute levels were selected on the basis of S1PR modulator product labels. In the MCDA, partial MCDA scores were created for each attribute and summed to produce an overall MCDA score for each S1PR modulator. The DCE was completed by 200 neurologists. The overall MCDA score was highest for ponesimod (4.78 points), followed by siponimod (4.10 points), fingolimod (3.61 points), and ozanimod (2.38 points). Having fewer drug-drug interactions contributed most to the overall scores (up to 1.56 points), followed by having no first-dose observations (0.95 points), the shortest immune system recovery time (0.94 points), and not interacting with foods high in tyramine (0.86 points). When considering clinical management convenience, the average US-based neurologist treating MS is likely to choose ponesimod over siponimod, fingolimod, or ozanimod. The strongest driver of preferences was the number of drug-drug interactions. This information can help inform recommendations for the treatment of MS and facilitate shared decision-making between clinicians and patients.

Drug Repurposing and Screening for Multiple Sclerosis Targeting Microglia and Macrophages.

Microglia/macrophages (MG/Mφ) play a central role in the pathogenesis of multiple sclerosis (MS). However, the intricacies of the immunomodulatory microenvironment in MS, particularly the heterogeneity and regulatory mechanisms of MG/Mφ subpopulations, remain elusive. The commonly used treatment options for MS have several drawbacks, such as significant side effects and uncertain efficacy. The exploration of developing new drugs targeting MG/Mφ for the treatment of MS remains to be investigated. We identified three distinct subpopulations of MG/Mφ, among which MG/Mφ_3 significantly increased as the experimental autoimmune encephalomyelitis (EAE) progressed. Ifenprodil and RO-25-6981 demonstrated notable inhibition of inflammatory factor expression, accompanied by reduced cytotoxicity. The interaction modes of these compounds with the common binding pocket in the GluN1b-GluN2B amino terminal domain heterodimer were elucidated. Virtual docking, based on the N-methyl-D-aspartate (NMDA) receptor, showed that homo-skeleton compounds of ifenprodil potentially exhibit low binding free energy with the receptor, including eliprodil and volinanserin. In vitro cell models corroborated the effective inhibition of inflammatory factor expression and minimal cytotoxicity of eliprodil and volinanserin. CoMFA (standard error of estimate = 0.378, R2 = 0.928, F values = 241.255, Prob. of R2 = 0) and topomer CoMFA (q2 = 0.553, q2 stderr = 0.77, intercept = - 1.48, r2 = 0.908, r2 stderr = 0.35) were established based on the inhibitors of NMDA receptor. The contour maps of CoMFA and topomer CoMFA models give structural information to improve the inhibitory function. This study underscores the involvement of MG/Mφ in inflammatory pathways during MS progression and offers promising compound candidates for MS therapy targeting MG/Mφ.

Recurrent late-onset neutropenia following treatment with different B cell-depleting strategies in multiple sclerosis.

As B cell-depleting therapies in multiple sclerosis (MS) have gained significant importance in the last several years, their long-term safety profile is of considerable clinical interest. Late-onset neutropenia (LON) is a rare, but potentially severe, adverse event that was first described in patients with rheumatic disorders under therapy with rituximab. Ofatumumab was approved in 2021 for the treatment of relapsing-remitting multiple sclerosis (RRMS). Neutropenia occurred in 0.2% of patients in clinical phase 3 trials, and to date, no cases of LON have been reported under ofatumumab treatment. Here, we report a case of repetitive symptomatic LON under ocrelizumab as well as ofatumumab treatment. Additionally, we review the literature on rare occurrences of LON in patients with MS, neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) undergoing B cell-depleting therapies, including rituximab, ocrelizumab, ofatumumab, inebilizumab, and ublituximab. In our case, the patient presented with repetitive symptomatic LON under ocrelizumab as well as ofatumumab treatment leading to febrile infections, subsequent use of antibiotics, and application of granulocyte-colony-stimulating factor. After repetitive episodes of LON under both B cell-depleting strategies, cladribine was subsequently initiated. A nine-month follow-up showed a normal neutrophil count and no evidence of disease activity. This case highlights the significance of symptomatic late-onset blood count changes under both ocrelizumab and ofatumumab and emphasizes the importance of continuous monitoring of the differential blood count under B cell-depleting treatment. This study was supported by the Deutsche Forschungsgemeinschaft (DFG; SFB CRC-TR-128 to F.Z., V.F., and S.B..; SFB 1080 and SFB CRC-1292 to F.Z..; and SFB/TRR 355 to S.B.) and the Hermann and Lilly Schilling Foundation (to S.B.).

Spatial transcriptomics of meningeal inflammation reveals inflammatory gene signatures in adjacent brain parenchyma.

While modern high efficacy disease modifying therapies have revolutionized the treatment of relapsing-remitting multiple sclerosis, they are less effective at controlling progressive forms of the disease. Meningeal inflammation is a recognized risk factor for cortical gray matter pathology which can result in disabling symptoms such as cognitive impairment and depression, but the mechanisms linking meningeal inflammation and gray matter pathology remain unclear. Here, we performed magnetic resonance imaging (MRI)-guided spatial transcriptomics in a mouse model of autoimmune meningeal inflammation to characterize the transcriptional signature in areas of meningeal inflammation and the underlying brain parenchyma. We found broadly increased activity of inflammatory signaling pathways at sites of meningeal inflammation, but only a subset of these pathways active in the adjacent brain parenchyma. Subclustering of regions adjacent to meningeal inflammation revealed the subset of immune programs induced in brain parenchyma, notably complement signaling and antigen processing/presentation. Trajectory gene and gene set modeling analysis confirmed variable penetration of immune signatures originating from meningeal inflammation into the adjacent brain tissue. This work contributes a valuable data resource to the field, provides the first detailed spatial transcriptomic characterization in a model of meningeal inflammation, and highlights several candidate pathways in the pathogenesis of gray matter pathology.

Spatial transcriptomics of meningeal inflammation reveals inflammatory gene signatures in adjacent brain parenchyma

While modern high efficacy disease modifying therapies have revolutionized the treatment of relapsing-remitting multiple sclerosis, they are less effective at controlling progressive forms of the disease. Meningeal inflammation is a recognized risk factor for cortical gray matter pathology which can result in disabling symptoms such as cognitive impairment and depression, but the mechanisms linking meningeal inflammation and gray matter pathology remain unclear. Here, we performed magnetic resonance imaging (MRI)-guided spatial transcriptomics in a mouse model of autoimmune meningeal inflammation to characterize the transcriptional signature in areas of meningeal inflammation and the underlying brain parenchyma. We found broadly increased activity of inflammatory signaling pathways at sites of meningeal inflammation, but only a subset of these pathways active in the adjacent brain parenchyma. Subclustering of regions adjacent to meningeal inflammation revealed the subset of immune programs induced in brain parenchyma, notably complement signaling and antigen processing/presentation. Trajectory gene and gene set modeling analysis confirmed variable penetration of immune signatures originating from meningeal inflammation into the adjacent brain tissue. This work contributes a valuable data resource to the field, provides the first detailed spatial transcriptomic characterization in a model of meningeal inflammation, and highlights several candidate pathways in the pathogenesis of gray matter pathology.

Real-World Experience with Diroximel Fumarate in Patients with Multiple Sclerosis: A Prospective Multicenter Study.

Current literature and a real-world study suggest that diroximel fumarate (DRF) is safer than dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS). However, no real-world study to date has significantly addressed the efficacy of this treatment. This study aims to elucidate the safety, tolerability, and efficacy of DRF in a real-world setting, utilizing data from a Spanish national registry of patients commencing DRF therapy post-market introduction. In this multicenter, prospective observational study, data were collected from MS patients who initiated DRF treatment. The study monitored demographic and clinical characteristics, safety outcomes (including adverse events, reasons for discontinuation, and lymphocyte counts), and efficacy outcomes (radiological and clinical activity). A total of 195 MS patients across 26 neurological departments were included, predominantly female (79.5%), with a mean age of 42.17 years, and a mean duration of treatment with DRF of 6.3 months. Most patients (70.3%) reported no adverse events, while gastrointestinal issues and flushing were the most common adverse events observed. The majority of patients (84.6%) continued with DRF treatment, with tolerability issues being the primary reason for discontinuation. Efficacy analysis showed low relapse rates post-DRF initiation, with most patients exhibiting stable or improved Expanded Disability Status Scale scores and radiological assessments demonstrating minimal activity. This comprehensive analysis provides valuable insights into the real-world application of DRF, confirming its safety and tolerability while offering preliminary evidence of its efficacy in managing MS.

Medicinal cannabis delivery systems: A perspective

In recent years, cannabis derivatives have been proposed for the treatment of various medical conditions, including pain, inflammation, epilepsy, sleep disorders, multiple sclerosis, anorexia, schizophrenia, neurodegenerative diseases, nausea, and cancer. While the benefits of cannabis derivatives, primarily cannabinoids, have been demonstrated and continue to be studied, their use presents various challenges associated with their low water solubility, rapid metabolism, erratic and poor bioavailability, and erratic pharmacokinetics, which directly affect their efficacy. In this context, a great deal of research is being carried out to overcome these drawbacks by designing delivery systems capable of improving solubility/bioavailability, potency, and efficacy, while addressing the purity and quality issues required by the pharmaceutical industry. This article aims to critically review the major trends and challenges in designing controlled-release cannabinoid delivery systems and their potential application in the pharmaceutical industry.

Inflammation-Targeted Biomimetic Nano-Decoys via Inhibiting the Infiltration of Immune Cells and Effectively Delivering Glucocorticoids for Enhanced Multiple Sclerosis Treatment.

Excessive infiltration of neutrophil and inflammatory cytokines accumulation as well as the inadequate delivery of drugs to the targeted site are key pathological cascades in multiple sclerosis (MS). Herein, inflammation-targeting biomimetic nano-decoys (TFMN) is developed that inhibit the infiltration of immune cells and effectively deliver glucocorticoids to lesions for enhanced MS treatment. Nano-decoys encapsulated with the glucocorticoid methylprednisolone (MPS) are prepared by coating neutrophil membrane (NM) on nanoparticles formed by the self-assembly of tannic acid and poloxamer188/pluronic68. Benefiting from the natural inflammation-targeting ability of activated neutrophil membranes, TFMN can target the lesion site and prevent neutrophils infiltration by adsorbing and neutralizing elevated neutrophil-related cytokines, subsequently modulating the inflammatory microenvironment in experimental autoimmune encephalomyelitis mice. TFMN exhibits a strong antioxidant capacity and scavenged excessive reactive oxygen species to enhance neuronal protection. Furthermore, at the inflammation site, perforin, discharged by cytotoxic T-lymphocytes, triggered the controlled release of MPS within the TFMN through perforin-formed pores in the NM. Simultaneously, this mechanism protected neurons from perforin-induced toxicity. The MPS liberated at the targeted site achieves optimal drug accumulation, thereby enhancing therapeutic efficacy. In conclusion, the innovative system shows potential for integrating various therapeutic agents, offering a novel strategy for CNS disorders.

MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) Tcell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients.

Efficacy and safety of cladribine tablets in multiple sclerosis in real-world clinical practice

Cladribine has a well-defined activity against lymphocytes, leading to their selective depletion.Objective: to determine the efficacy and safety of cladribine in the treatment of multiple sclerosis (MS) in real-world clinical practice.Material and methods. The study involved 82 patients (57 women and 25 men, mean age 36.4±9.3 years) with a disease duration of 2.2±1.5 years. Seven (9%) patients had secondary progressive MS (SPMS), 6 (7%) had rapidly progressive MS (RPMS) and 69 (84%) had highly active MS (HAMS). According to the instructions for use, oral therapy with cladribine was administered in two short courses (up to 10 days per year) to achieve a long-term effect on the immune system. The dose of cladribine was calculated based on the body weight.Results. The average frequency of exacerbations per year before starting therapy was 1.6, while it decreased to 0.2 during cladribine therapy. An exacerbation was observed in 18 patients (22%) at the end of the first course of cladribine treatment and in one patient (2.6%) after the second treatment course. Thus, the number of exacerbations decreased by 78% after the first year of treatment and by 97.4% after the second year of treatment. The mean EDSS score was 3.2±2.5 points before the start of treatment, 3.6±2.5 points after the first course of treatment and 3.4±2.5 points after the second course (p&gt;0.05). MRI results showed a decrease in disease activity by 83% after the first course of cladribine therapy and by 97.4% after the second course. No serious adverse events occurred in any of the patients.Conclusion. We demonstrated efficacy and safety of cladribine in real-life clinical practice in MS patients with frequent exacerbations and rapid disability progression (SPMS, RPMS, HAMS).

RNA Binding Protein Dysfunction Links Smoldering/Slowly Expanding Lesions to Neurodegeneration in Multiple Sclerosis.

Despite the advances in treatments for multiple sclerosis (MS), unremitting neurodegeneration continues to drive disability and disease progression. Smoldering/slowly expanding lesions (SELs) and dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) are pathologic hallmarks of MS cortex and intricately tied to disability and neurodegeneration, respectively. We hypothesized that neuronal hnRNP A1 dysfunction contributes to neurodegeneration and is exacerbated by smoldering/SELs in progressive MS. Neuronal hnRNP A1 pathology (nucleocytoplasmic mislocalization of hnRNP A1) was examined in healthy control and MS brains using immunohistochemistry. MS cases were stratified by severity of hnRNP A1 pathology to examine the link between RBP dysfunction, demyelination, and neurodegeneration. We found that smoldering/SELs were only present within a subset of MS tissues characterized by elevated neuronal hnRNP A1 pathology (MS-A1high) in adjacent cortical gray matter. In contrast to healthy controls and MS with low hnRNP A1 pathology (MS-A1low), MS-A1high showed elevated markers of neurodegeneration, including neuronal loss and injury, brain atrophy, axonal loss, and axon degeneration. Additionally, we discovered a subpopulation of morphologically intact neurons lacking expression of NeuN, a neuron-specific RBP, in cortical projection neurons in MS-A1high cases. hnRNP A1 dysfunction contributes to neurodegeneration and may be exacerbated by smoldering/SELs in progressive MS. The discovery of NeuN-negative neurons suggests that some cortical neurons may only be injured and not lost. By characterizing RBP pathology in MS cortex, this study has important implications for understanding the pathogenic mechanisms driving neurodegeneration, the substrate of disability and disease progression. ANN NEUROL 2024.