RARE DISEASE
Neuromyelitis optica spectrum disorder
Neuromyelitis optica spectrum disorder
Neuromyelitis optica spectrum disorder
Synonyms: Devic disease, NMOSD
Synonyms: Devic disease, NMOSD
Synonyms: Devic disease, NMOSD
Drug discovery
10
drugs
With orphan designations
Overview
Neuromyelitis Optica Spectrum Disorder (NMOSD) is a rare autoimmune condition primarily targeting aquaporin-4 (AQP4) water channels in the central nervous system, causing optic neuritis, transverse myelitis, and brainstem syndromes. It leads to severe disability through relapses, with symptoms such as vision loss, paralysis, and autonomic dysfunction. Diagnosis requires MRI and AQP4-IgG serology, distinguishing it from multiple sclerosis. Early immunosuppression is critical to limit attack severity and relapse frequency.
Population
Prevalence: 1–12.99/100,000, with higher rates in Black (12.99) and Asian (9.41) populations vs. White individuals (5.58) [2][10].
Demographics: 90% female predominance; median age of onset ~40 years (AQP4-IgG+), earlier in non-White groups [1][10][14].
Comorbidities: Often linked with systemic autoimmune diseases (e.g., lupus, Sjögren’s) [9][14].
Burden
Disability: ≥65% of relapses require hospitalization; 15.4% mortality in Black vs. 7% overall [10][11].
Economic impact: High costs from recurrent hospitalizations, biologics, and long-term care [4][15].
Quality of life: Chronic pain, vision loss, and mobility deficits contribute to depression and unemployment [4][13].
Therapies
Acute attacks: High-dose IV corticosteroids ± plasma exchange (PLEX) for refractory cases [3][7].
Relapse prevention: First-line immunosuppressants (rituximab, mycophenolate mofetil) and FDA-approved biologics (eculizumab, inebilizumab, satralizumab) targeting complement, CD19/20, or IL-6 pathways [3][15].
Monitoring: Regular clinical/MRI assessments to adjust therapy and detect subclinical activity [7][15].
Categories: rare neurological diseases, rare ophthalmic disorders
Research Papers
1,854 drug discovery papers about Neuromyelitis optica spectrum disorder, with 5 first-in-class and 18 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,854 drug discovery papers about Neuromyelitis optica spectrum disorder, with 5 first-in-class and 18 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-29 | Case Report: Confirmed and suspected heparin-induced thrombocytopenia during therapeutic plasma exchange in neuromyelitis optica spectrum disorder: a single-centre case series.
Neuromyelitis optica spectrum disorder (NMOSD) is a B-cell-mediated autoimmune disease associated with aquaporin-4 (AQP4-IgG) antibodies in which patients may require anticoagulation, including heparin for venous thromboembolism prophylaxis, thereby exposing them to a risk of heparin-induced thrombocytopenia (HIT), an immune-mediated complication caused by antibodies directed against PF4-heparin complexes. Whether anti-AQP4-mediated autoimmunity contributes to susceptibility to anti-PF4/heparin immune responses warrants further investigation. Four cases of suspected or confirmed HIT in patients with NMOSD are presented, together with a review of the current literature. In our NMOSD cohort (n=90), 24 patients underwent therapeutic plasma exchange (TPE), among whom HIT was suspected in four cases (16,7% suspected and 8.3% immunoassay positive). These findings underscore the need for vigilance regarding HIT and thromboembolic complications in NMOSD patients undergoing relapse treatment with TPE. Strategies for the safe continuation of TPE using non-heparin anticoagulation and considerations for outpatient management are also addressed. Awareness of this potential association may facilitate earlier recognition and appropriate management in clinical practice.
2026-09-29 | Metabolic reprogramming in neuromyelitis optica spectrum disorder: From astrocyte dysfunction to immune-mediated neuroinflammation.
Neuromyelitis optica spectrum disorders comprise a group of autoimmune diseases of the central nervous system, defined primarily by astrocyte injury mediated by anti-aquaporin-4 antibodies. Although targeted therapies directed against B cells, complement, and inflammatory mediators have substantially reduced the relapse risk in recent years, a subset of patients still exhibits persistent neurological impairment. Recent advances in immunometabolic research suggest that metabolic reprogramming may be a potentially important regulatory process linking immune abnormalities to neurological damage.This review synthesizes the current understanding of metabolic abnormalities and their underlying mechanisms in NMOSD from an immunometabolic perspective, with a particular focus on the interplay between astrocyte damage and disruption of metabolic homeostasis. Current research suggests that AQP4-IgG-mediated astrocyte dysfunction may disrupt the metabolic support network of the central nervous system, which in turn may lead to energy metabolism disorders and mitochondrial dysfunction, and further affect the metabolic state of immune cells. Metabolically reprogrammed T cells and B cells may exhibit functional shifts, which could contribute to the persistence of inflammation and the progression of tissue damage.Among these, metabolic regulatory pathways, including mTOR, AMPK, and HIF-1α, appear to participate in metabolic adaptation and immune regulation across various cell types. Based on these findings, targeting the regulatory networks of glycolysis, mitochondrial homeostasis, and immunometabolic regulation may offer new therapeutic approaches for NMOSD; however, most intervention strategies are still in the experimental exploration phase.Research into metabolic reprogramming in NMOSD remains in its nascent stages. Future investigations, integrating multi-omics approaches and relevant disease models, will be essential to further identify key metabolic targets and to explore the potential synergy between metabolic interventions and existing immunotherapies.
2026-09-22 | Micheliolide and ACT001 as Covalent Modulators of Inflammation-Redox-Metabolism Networks in CNS Disorders: An Evidence-Stratified Review of Mechanisms and Translational Challenges.
Micheliolide (MCL), a guaianolide sesquiterpene lactone bearing an α-methylene-γ-lactone Michael acceptor pharmacophore, and its orally bioavailable prodrug ACT001 have been studied in a growing range of central nervous system (CNS) disorders, including traumatic brain injury, Parkinson's disease, neuropathic pain, neuromyelitis optica spectrum disorder, and glioblastoma. These compounds act beyond classical pathway inhibition (that is, blockade of any single linear signalling cascade in isolation) by modulating interconnected inflammatory, redox, and metabolic signalling modules. This review integrates preclinical evidence across CNS disease models and proposes a unified three-axis framework-encompassing innate immune-inflammatory regulation, redox homeostasis, and metabolism-associated signal integration-to organise mechanistic findings, stratify evidence by direct CNS validation status, and identify translational gaps. This review is based on a structured search of PubMed and Web of Science for publications on micheliolide, DMAMCL, or ACT001 in central nervous system disorders, and the diseases are discussed in the sequence in which the supporting evidence is presented below. The inflammatory axis (NF-κB/NLRP3/TLR4/MD2/STAT3) is the best-supported CNS-relevant mechanism, with convergent evidence across traumatic brain injury, Parkinson's disease, neuropathic pain, and glioblastoma, including direct binding to the TLR4 co-receptor MD2 and IKKβ. Redox modulation (KEAP1/NRF2) remains plausible but rests primarily on peripheral models, awaiting CNS validation. The metabolism-associated axis (PKM2, GAPDH, MDK/c-Myc) is an innovative but incompletely validated frontier, with GAPDH Cys247 covalent engagement in glioblastoma as the strongest direct CNS evidence. We propose a disease-stratified model-neurodegeneration as inflammation-dominant, acute brain injury as inflammation-metabolism coupled, autoimmune and pain conditions as glial-lineage-expanded, and brain tumours as multi-axis dysregulated-requiring experimental validation. Although glioblastoma is the most translationally advanced indication for this chemotype, the shared neuroinflammatory, redox, and metabolic mechanisms engaged by MCL/ACT001 provide a strong rationale for their evaluation across non-malignant CNS disorders. MCL and ACT001 represent a promising covalent scaffold for modulating interconnected CNS networks, with glioblastoma as the most translationally advanced indication. Priorities include quantitative CNS pharmacokinetics, long-term safety of covalent pharmacology in post-mitotic neurons, and validation of metabolic-redox coupling in brain-resident cells via chemoproteomic and single-cell approaches.
2026-09-20 | Potential links between gut microbiota-derived propionate and succinate and CXCL8, IL1B, and IL6 in NMOSD: An integrated network pharmacology and mendelian randomization study.
Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune demyelinating disease of the central nervous system. Gut microbiota metabolites may participate in NMOSD pathogenesis, but their biological relevance and underlying molecular links remain unclear. Candidate key targets of gut microbiota metabolites in NMOSD were obtained from the intersection of public database targets (human gut, NMOSD, and metabolite targets). Functional enrichment and regulatory network analyses were conducted. Microbiota-metabolite-target-signaling pathway (MMTS) network, Mendelian randomization (MR) analysis, and metabolite evaluations (drug-likeness, toxicology, and molecular docking) were performed. CXCL8, IL1B, and IL6 were identified as candidate key targets. Notably, they were enriched in pathways related to immune regulation and inflammatory responses, such as "NOD-like receptor signaling pathway", "Toll-like receptor signaling pathway", and "IL-17 signaling pathway". Predicted regulatory factors included hsa-miR-191-5p and hsa-let-7c-5p. Additionally, Barnesiella intestinihominis, Ruminococcus bromii, and Ruminococcus champanellensis were identified as key microbiota. Their associated key metabolites, including propionate and succinate, exhibited favorable drug-likeness, low toxicity, and promising binding affinities to the candidate key targets. This study suggests that gut microbiota metabolites may affect NMOSD through CXCL8, IL1B, IL6, and immune-inflammatory pathways. Propionate and succinate were identified as candidate metabolites requiring experimental validation of their effects on these targets.
2026-09-03 | The cGAS-STING Pathway: A Double-Edged Regulator of Neuroinflammation and Myelin Regeneration.
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA sensor that mediates innate immunity by inducing type I interferons (IFN-I) and proinflammatory cytokines. Although its role in antiviral defense and tumor immunity has been well established, emerging evidence suggests that it is also closely involved in demyelinating diseases of both the central and peripheral nervous systems (PNS). Such diseases, exemplified by multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), are characterized by immune-mediated inflammation, oxidative stress, mitochondrial dysfunction, and impaired myelin regeneration. This review systematically examines the diverse roles of the cGAS-STING pathway in demyelination. We summarize how moderate activation of this pathway promotes protective inflammation and autophagy, facilitating debris clearance and supporting remyelination during the early stages of disease. In contrast, excessive or sustained activation exacerbates neuroinflammation, hinders remyelination, and promotes progressive axonal injury. The involvement of cGAS-STING in T cell polarization, reactive oxygen species (ROS)-mediated injury, and antiviral responses further underscores its dual role in both disease initiation and progression. Understanding the context-dependent effects of cGAS-STING signaling in demyelinating diseases offers valuable insights for developing targeted therapeutic strategies. However, this review also emphasizes that most current evidence is derived from cellular and animal models. Given that the effects of cGAS-STING signaling are highly context dependent and may vary among different demyelinating diseases, disease stages, and cell types, further clinically relevant studies are required to validate its therapeutic potential.
antibodies
2026-09-30 | Optimizing the management of AQP4 antibody-positive NMOSD: A Canadian consensus.
Aquaporin-4-IgG-positive (AQP4+) neuromyelitis optica spectrum disease (NMOSD) is a rare demyelinating disorder/astrocytopathy with an estimated prevalence of 1 per 100,000 population in Canada. An expert panel of Canadian clinicians developed consensus recommendations for the diagnosis and treatment of AQP4+ NMOSD to optimize patient outcomes. Panel co-chairs (DLR, MSF) developed recommendations for voting by the 18 consensus group members using a modified e-Delphi method. Statements with an average >4.25 on a 5-point Likert-type scale were adopted. Consensus was achieved for 25 of 27 recommendations on the first round of voting; two recommendations achieved consensus after revision with a second round of voting. There was consensus on the application of current international criteria for the diagnosis of AQP4+ NMOSD in pediatric and adult patients; use of a live or fixed cell-based assay to detect AQP4 antibodies; urgent early use of intravenous methylprednisolone and plasma exchange for acute attacks; use of a prednisone taper until dosing of a maintenance therapy is optimized; and initiation of long-term maintenance therapy with a monoclonal antibody therapy. It was recommended that vaccination status be checked and vaccinations updated, including administration of any missing non-live vaccinations in patients on prednisone following a relapse. There was consensus that treatment should be maintained long-term since discontinuation is associated with considerable risk of potentially disabling relapses regardless of age and/or disease stability. It is hoped that this expert consensus will help guide the management of AQP4+ NMOSD patients and improve long-term outcomes.
2026-09-29 | Diagnostic delay and poor functional outcomes in late-onset NMOSD: A Thai cohort study.
Late-onset neuromyelitis optica spectrum disorder (LONMOSD) may be difficult to recognize because symptoms can mimic other neurological disorders in older patients. Data on LONMOSD in Thailand remain limited. To compare clinical characteristics and outcomes between early-onset NMOSD (EONMOSD) and LONMOSD in a Thai cohort, and to evaluate the impact and causes of delayed diagnosis in LONMOSD. We retrospectively studied adult patients with NMOSD who fulfilled the 2015 International Panel for NMO Diagnosis criteria at a tertiary referral center in Thailand from 2016 to 2025. LONMOSD was defined as onset at age ≥50 years. Clinical characteristics, treatment, Expanded Disability Status Scale (EDSS), relapse outcomes, and reasons for delayed diagnosis were analyzed. Among 148 patients, 91 had EONMOSD and 57 had LONMOSD. LONMOSD was associated with more frequent delayed diagnosis than EONMOSD (54.4%vs 31.9%, P = 0.01). LONMOSD patients had higher EDSS at nadir, 90 days, and 180 days, and lower recovery index at 180 days. Relapse outcomes and time to subsequent relapse were not significantly different between groups. In LONMOSD, myelitis was independently associated with EDSS ≥6 at 90 and 180 days, while delayed diagnosis was associated with EDSS ≥6 at 90 days. Misdiagnosis was the main cause of delayed diagnosis, most commonly cerebrovascular disease and compressive myelopathy. LONMOSD was associated with delayed diagnosis and worse functional outcomes. Early recognition may reduce preventable disability in older patients.
2026-09-12 | Recognition and management of acute relapse of multiple sclerosis, neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease.
Autoimmune diseases of the central nervous system include multiple sclerosis (MS) and an ever-expanding spectrum of related disorders, such as neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Despite differences in targeted neuroantigens and immune effector mechanisms, these disorders share a common clinical pattern: acute neurological episodes, typically termed attacks at the onset, and relapses during the disease course. Timely recognition of an acute attack or relapse is challenging, not only because of discrepancies between patient-reported and physician-affirmed neurological symptoms, but also due to other confounding factors, such as comorbidities, treatment-related side effects, and transient symptom fluctuations unrelated to underlying disease. Once an attack/relapse is recognized, prompt initiation of treatment is essential, as responsiveness to treatment at the acute stage largely determines the long-term neurological outcomes. In this review, we focus on MS, NMOSD and MOGAD, and discuss the clinical patterns of acute attacks and relapses, including the clinical and para-clinical modalities that are critical for timely recognition and diagnosis. We present the available evidence regarding treatment selection and responsiveness for three categories of therapy: intravenous methylprednisolone (IVMP), intravenous immunoglobulin (IVIG), and plasma exchange/immunoadsorption (PLEX/IA). Notably, we update ongoing clinical trials that incorporate fast-acting, targeted biologic complement inhibitors and neonatal Fc receptor (FcRn) antagonists. We discuss potential drivers of relapses and emerging mechanism-guided interventions for acute management. Finally, we call for international collaborative efforts in this important yet under-investigated area to establish clear criteria for relapse, with the ultimate goal of developing more effective therapies.
2026-09-09 | Right Knee Ureaplasma Septic Arthritis in an Immunocompromised Host, Requiring Right Hip Disarticulation for Definitive Source Control.
Ureaplasma urealyticum is a fastidious, urease-producing bacterium typically responsible for urogenital infections. In immunocompromised hosts, a full-thickness mucosal breach may be complicated by hematogenous spread, leading to septic arthritis in distant joints U. urealyticum is difficult to isolate on routine culture and requires special media or 16S rRNA polymerase chain reaction for detection. We report a 26-year-old immunocompromised female with neuromyelitis optica on long-term cyclosporine and Grave's disease, who developed chronic right knee U. urealyticum septic arthritis. She presented with the right calf pain; knee aspiration was turbid but culture-negative on routine testing. Despite 6 weeks of empirical antibiotics, symptoms persisted, and arthroscopic biopsy with 16S molecular testing eventually identified U. urealyticum. She was treated with multiple antibiotic regimens, including intravenous (IV) aztreonam, vancomycin, oral levofloxacin, and IV azithromycin, and her immunosuppression was reduced. Despite this, she developed medial tibial plateau osteomyelitis, an intra-articular abscess, and a sinus tract, requiring multiple debridements, cement spacer insertion, external fixation, and eventually two-stage revision knee replacement with flap reconstruction. Cultures remained persistently positive for U. urealyticum despite prolonged therapy and repeated surgery. One year after the index revision attempt, she underwent above-knee amputation for source control, followed by hip disarticulation 1 month later due to persistent stump infection. With aggressive wound care, including negative pressure wound therapy and staged dressing de-escalation, the wound achieved complete healing. She was discharged 180 days after hip disarticulation and, at 2-year follow-up, was ambulant with a hip prosthesis, independent in activities of daily living, and had returned to work. This case highlights the diagnostic challenge and potential severity of U. urealyticum septic arthritis in immunocompromised hosts, which may progress to refractory osteomyelitis and necessitate radical surgical measures, including amputation, for definitive source control despite prolonged targeted antibiotic therapy.
2026-09-02 | HLA polymorphism in neuroimmune diseases: linking antigen presentation to neuroinflammatory programs.
Human leukocyte antigen (HLA) polymorphism shapes antigen presentation and susceptibility to immune-mediated disease. In neuroimmune disorders, a central question is how HLA-dependent antigen visibility becomes disease-specific immunity and tissue injury. In this Review, we integrate genetic, molecular, cellular, and clinical evidence across multiple sclerosis (MS), neuromyelitis optica spectrum disorder, Guillain-Barré syndrome, narcolepsy, autoimmune encephalitis, and myasthenia gravis. The HLA-DR15-MS axis is the most mechanistically resolved example, linking allele-specific peptide display to autoreactive T-cell repertoires and convergent Epstein-Barr virus-related immune pathways. In other disorders, this upstream principle operates through distinct effectors, target tissues, molecular subtypes, and ancestral contexts, while causal peptide-receptor complexes often remain unresolved. We therefore separate association strength from mechanistic resolution and position glial activation and tissue injury mainly as downstream, context-dependent processes. This evidence-bounded synthesis identifies where HLA mechanisms are established, suggestive, or still inferred from association.
proteins
2026-08-08 | Complement C3 inhibitory peptide AMY-101 ameliorates brain injury in a mouse model of NMOSD.
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory demyelinating disease of the central nervous system, clinically characterized primarily by optic neuritis and transverse myelitis. This study aimed to investigate the therapeutic potential of the complement C3 inhibitory peptide AMY-101 in experimental models of NMOSD. In vitro experiments were performed using AQP4-transfected cells exposed to AQP4-IgG and human complement to assess complement-dependent cytotoxicity and membrane attack complex (MAC) deposition. In vivo efficacy was evaluated in an intracerebral injection mouse model of NMOSD, in which histopathological changes after AMY-101 treatment were compared with those in untreated controls. AMY-101 significantly attenuated AQP4-IgG- and complement-mediated cytotoxicity and inhibited MAC formation in vitro. In the NMOSD mouse model, AMY-101 treatment markedly reduced astrocyte loss, AQP4 depletion, and demyelination compared with controls. These findings demonstrate that complement C3 inhibition with AMY-101 effectively ameliorates key pathological features of NMOSD in experimental models, supporting its potential as a therapeutic strategy and providing a rationale for further preclinical and clinical investigation.
2026-07-15 | Ferritin-ApoE nanocarrier for targeted therapy of neuromyelitis optica spectrum disorder in mice.
Neuromyelitis optica spectrum disorder (NMOSD) is a chronic inflammatory autoimmune disease affecting the central nervous system (CNS), characterized by anti-aquaporin 4 (AQP4) antibody-mediated damage to astrocytes, resulting in subsequent demyelination. Our prior work identified the protective effects of the apolipoprotein E130-149 (ApoE130-149) peptide in NMOSD mice by promoting astrocyte-microglia intercellular communication. However, its therapeutic potential is restricted due to the limited penetration of the blood-brain barrier (BBB) with systemic administration. Here, we designed a heavy-chain ferritin (HFn)-based nanocarrier containing the ApoE130-149 peptide (HFn-ApoE130-149), specifically engineered for CNS delivery. HFn-ApoE130-149 was constructed through genetic engineering by fusing the coding sequence of HFn with that of the ApoE130-149 peptide in a recombinant plasmid. An acute NMOSD mouse model was induced by transcranial co-injection of AQP4-IgG and human complement (hC) into the brain. The distribution of Cy5.5-labeled HFn-ApoE130-149 post intravenous injection was tracked using in vivo fluorescence imaging to confirm its presence in the brain and peripheral organs. Lesions in the brain were quantified using T2-weighted 7 Tesla magnetic resonance imaging (7T-MRI). Neuropathological features of NMOSD were evaluated by immunostaining of brain sections. Neuroinflammation and immune cell infiltration were analyzed via flow cytometry. The key signaling pathways regulated by HFn-ApoE130-149 were investigated through Western blot (WB) analysis. The interaction between HFn-ApoE130-149 and its receptors was validated through co-immunoprecipitation and visualized on microglia using proximity ligation assay (PLA). Finally, the therapeutic effect on spatial learning and memory was evaluated using the Morris water maze (MWM) test. The HFn-ApoE130-149 effectively crossed the BBB, attenuated lesion progression and demyelination, as well as preserved AQP4 expression and astrocytic integrity in NMOSD mice. The treatment induced a spatial and phenotypic restructuring of the astrocytic response, notably reducing excessive astrocyte accumulation around lesions while encouraging a proliferative and reparative phenotype. Furthermore, HFn-ApoE130-149 influenced microglial polarization towards an anti-inflammatory state, reducing infiltration of peripheral immune cells. Mechanistically, HFn-ApoE130-149 exerted its anti-inflammatory effects through the low-density lipoprotein receptor-related protein 1 (LRP1) -nuclear factor kappa B (NF-κB) signaling axis in microglia. Functional binding of HFn-ApoE130-149 to LRP1 suppressed inhibitor of NF-κB (IκBα) phosphorylation, thereby inhibiting NF-κB nuclear translocation and the subsequent release of pro-inflammatory cytokines, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Knocking down LRP1 reversed these effects, highlighting the importance of the LRP1-NF-κB signaling axis in the nanotherapeutic's efficacy. Treatment with HFn-ApoE130-149 improved spatial learning and rescued memory deficits in NMOSD mice. This study demonstrates that the engineered nanodrug HFn-ApoE130-149 is a promising targeted therapy for alleviating NMOSD pathology by enhancing BBB penetration and suppressing neuroinflammation through the LRP1-NF-κB signaling axis.
2026-02-13 | Therapeutic immune tolerance for central nervous system autoimmune diseases - Prospects, challenges and pitfalls.
Autoimmune diseases of the central nervous system (CNS), including multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), are characterized by chronic inflammation driven by autoreactive immune responses against CNS antigens. Successes in the development of efficacious immunotherapies are hampered by the risks of broad immunosuppression and the consequences of compromising physiological immune functions. Antigen-specific immune tolerance offers a promising alternative by selectively silencing pathogenic immune responses while preserving global immune competence. Advances in understanding of pathophysiology and target antigens in multiple sclerosis, neuromyleitis optica spectrum disroders (NMOSD) myelin oligondendrocyte protein (MOG) antibody associated disease (MOGAD) have enabled the development of antigen-based tolerization strategies. These approaches primarily act through restoration of peripheral tolerance via modulation of autoreactive T and B cell responses. Clinical trials in MS and NMOSD have provided critical insights into key challenges of translation and clinical development, including optimal antigen selection, route of administration, patient stratification and trial design constraints. Future progress in MS, NMO and MOGAD will also depend on precise characterization of immunodominant epitopes and the development of standardized biomarkers of tolerance induction and their integration in novel trial designs. Successful induction of durable, antigen-specific immune tolerance would represent a paradigm shift in treating CNS autoimmunity, enabling disease-specific, safe, and sustained remission without generalized immunosuppression.
2026-01-28 | Therapeutic effects of IGF-2 on NMOSD by inhibiting astrocyte apoptosis through modulation of the IGF-1R/PI3K/AKT signaling pathway.
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease characterized by the presence of antibodies specific to the aquaporins 4 (AQP4) protein. The complexity of its pathogenesis poses significant challenges to treatment, which remains both limited and costly. Consequently, there is an urgent need to elucidate the pathogenesis of NMOSD and to develop novel therapeutic strategies. Here, through a proteomic screen of serum from AQP4-IgG-positive NMOSD patients and a control cohort, we observed a significant downregulation of Insulin-like growth factor 2 (IGF-2) in the serum of AQP4-IgG-positive NMOSD patients and correlated with disease severity. Injecting adenovirus overexpressing IGF-2 into the brains of NMOSD mice reduced microglia, neuroinflammation, and brain injury. Both in vivo and in vitro experiments show IGF-2 activates the IGF-1R/PI3K/AKT pathway, reducing apoptosis and inflammation. These findings highlight IGF-2 as a promising target for NMOSD diagnosis and treatment, offering new insights into disease mechanisms and potential interventions.
2025-10-13 | Size of aquaporin-4 orthogonal arrays of particles are affected by the palmitoylation state of the M1 isoform.
Human aquaporin-4 (AQP4) is a water-channel protein crucial for water-ion homeostasis in the central nervous system. Dysregulation of AQP4 function is linked to neurological conditions like brain edema, neuromyelitis optica, and epilepsy. AQP4 has two isoforms, M1 and M23. The M23 isoform forms large structures known as Orthogonal Arrays of Particles (OAPs), while M1 coats the outer surface of OAPs. The dynamics of OAP aggregation may modulate water permeability and ion homeostasis in the brain. This study shows that the palmitoylation state of M1 influences OAP self-assembly, with depalmitoylated M1 producing OAPs 20 % larger than those formed by palmitoylated M1 at the same concentration. This, along with prior research on M1 aggregation, suggests palmitoylated M1 forms a single outer layer arounf OPAs, whereas depalmitoylated M1 creates a double layer. Single-particle tracking was used to study M23 OAP formation in lipid bilayers under equilibrium conditions. Our data support the idea that M1 regulates M23 OAP size, showing that average OAP size decreases as M1 concentration increases. This study explores the inhibitory effects of M1 on AQP4 M23 assembly and how M1's palmitoylation state affects OAP size regulation. These insights could lead to new therapeutic approaches for managing AQP4 assembly and function in related conditions.
cell therapies
2026-09-25 | Stem Cell-Based Therapies for Central Nervous System Demyelinating Diseases: Clinical Evidence, Therapeutic Niches, and Translational Boundaries.
Central nervous system demyelinating disorders differ substantially in pathobiology, reversibility, and capacity for tissue repair. Disease-modifying therapies can suppress inflammatory activity in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), but they do not replace lost oligodendrocytes or reliably reverse established neuroaxonal injury. Stem cell-based strategies therefore pursue distinct therapeutic goals, including immune reconstitution, paracrine immunomodulation and neuroprotection, direct cell replacement, remyelination, and correction of defined genetic defects. Autologous hematopoietic stem cell transplantation (AHSCT) currently has the most mature clinical evidence, particularly for carefully selected patients with highly active relapsing MS despite high-efficacy therapy, but its benefit is mediated primarily through immune ablation and reconstitution rather than direct remyelination. Mesenchymal stromal cell (MSC) approaches remain investigational because controlled trials have not established consistent efficacy and intrathecal delivery has raised route-specific safety concerns. MSC-derived extracellular vesicles and induced pluripotent stem cell (iPSC)-derived oligodendrocyte or neural progenitor products remain preclinical or early translational approaches for acquired demyelinating disease, whereas gene-modified hematopoietic stem cells have a distinct role in selected inherited leukodystrophies. Translation across these platforms is additionally constrained by product heterogeneity, potency assessment, manufacturing reproducibility, long-term safety, regulation, scalability, access, and the need for mechanism-matched clinical endpoints. This article aims to critically review the clinical evidence, therapeutic niches, safety considerations, and translational boundaries of stem cell-based therapies for central nervous system demyelinating diseases, with particular emphasis on MS and NMOSD.
2026-09-16 | Regulatory T cells as drivers of CNS remyelination: neuro-immune cross-talk and comparative insights from mammalian and zebrafish models.
Demyelination of the Central Nervous System (CNS) is a pathological process that causes the destruction of the myelin sheath, the insulating cover that protects the nerve fibres. This serves as one of the major attributes of numerous neurological disorders, such as Multiple Sclerosis (MS), Neuromyelitis Optica Spectrum Disorder (NMOSD), Acute Disseminated Encephalomyelitis (ADEM), Myelin Oligodendrocyte Glycoprotein-related antibody disease (MOGAD), etc. It is usually initiated as an immune-mediated injury to myelin, followed by dysregulation of the immune system and ultimately failure of effective remyelination. Although oligodendrocytes in the CNS have some capacity for regeneration, the surrounding microenvironment severely inhibits their function, which results in a reduced regenerative outcome. Previously referred to as suppressor T cells, regulatory T cells (Tregs) are a subset of T cells that were traditionally thought to have an immunosuppressive function. However, it has just recently been shown that they directly contribute to regeneration and repair. The goal of this review is to demonstrate how Tregs can promote regeneration by balancing a variety of underlying molecular and cellular processes. Recent research shows that Tregs affect oligodendrocyte lineage progression, microglial and astrocytic responses, and the milieu around the demyelination site in order to perform remyelination. These effects are age-dependent and occur both temporally and geographically. In order to offer an evolutionary perspective on the conserved immune-mediated regenerative pathways that may be diminished in mammals and can be further investigated for therapeutic purposes, this review also aims to draw comparisons between the mechanisms used by regeneration-competent and non-competent species.
2026-08-18 | Therapeutic Plasma Exchange in Neuromyelitis Optica Spectrum Disorder: Real-World Clinical Outcomes and Safety From a Tertiary Care Center in Northwest India.
Neuromyelitis Optica Spectrum Disorder (NMOSD) is a severe autoimmune demyelinating disorder of the central nervous system characterized by relapsing attacks that can result in permanent neurological disability. Therapeutic Plasma Exchange (TPE) is recommended for steroid-refractory acute exacerbations. This study evaluated the efficacy and safety of TPE in patients with acute NMOSD attacks. A prospective observational study was conducted over 18 months at SMS Jaipur, India. Forty adult patients fulfilling the 2015 International Panel for NMO Diagnosis criteria and presenting with steroid-refractory acute attacks were enrolled. TPE was performed using continuous-flow centrifugation, exchanging 1.0-1.4 estimated plasma volumes per session for 3-7 alternate-day procedures. Clinical outcomes were assessed using the EDSS, Snellen visual acuity, and MRC muscle strength grading. The cohort had a female predominance (65.0%) with a mean age of 36.5 years. Acute first presentations accounted for 77.5% of cases, while 22.5% were relapses. Anti-aquaporin-4 antibody positivity was detected in 45.0% of patients. Among 37 patients with motor deficits, 94.6% showed clinical improvement following TPE, including marked (35.1%), moderate (43.2%), and mild (16.2%) responses. Mean EDSS improved significantly from 7.4 to 4.1 (95% CI and p < 0.001). Visual improvement was observed in 84.4% of patients with baseline visual impairment. Adverse events occurred in 25.0% of patients, predominantly transient hypotension and mild citrate-related hypocalcemia, with no procedure-related treatment discontinuation. TPE is a safe and effective rescue therapy for steroid-refractory NMOSD exacerbations, producing substantial neurological and visual recovery with a favorable safety profile.
2026-08-05 | Association of therapeutic plasma exchange with functional outcomes in selected neurological disorders: a retrospective cohort study from a single tertiary center in Saudi Arabia.
Neurological disorders are associated with considerable morbidity and healthcare impact. Therapeutic plasma exchange (TPE) is an intervention that removes pathogenic antibodies, immune complexes, and other plasma constituents from circulation. Previous studies have suggested that TPE could be associated with improved outcomes in selected neurological disorders. To evaluate functional outcomes following therapeutic plasma exchange in patients with selected neurological disorders at National Guard Health Affairs (NGHA) in Jeddah, Saudi Arabia. This retrospective cohort study analyzes 133 patients diagnosed with various neurological disorders who received TPE between August 2015 and December 2022 at NGHA. Diagnoses included multiple sclerosis (MS), myasthenia gravis (MG), Guillain-Barré syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), chronic inflammatory demyelinating polyneuropathy (CIDP), autoimmune encephalitis (AE), and other neurological conditions including amyotrophic lateral sclerosis (ALS), transverse myelitis, cerebellar ataxia, paraneoplastic neurologic syndrome, polymyositis, and central nervous system (CNS) infections. The effectiveness of TPE was assessed using the Modified Rankin Scale (mRS) before and 90 days following the final TPE session. Statistical analysis included Wilcoxon signed-rank tests and Mann-Whitney U test, with significance set at (p < 0.05). Significant improvements in mRS scores were observed following TPE for MS, MG, and GBS (all p < 0.001), as well as for NMOSD (p = 0.008), CIDP (p = 0.007), and AE (p = 0.018), but not in other neurological disorders (p = 0.234). Overall mortality was 6.8%, with no TPE-related deaths. Comorbidities among deceased patients included hypertension, diabetes mellitus, malignancy, chronic kidney disease, and cardiovascular disease. TPE was associated with improved functional outcomes in selected neurological disorders. Comorbidities were common among patients with poorer outcomes. Due to the retrospective design and potential confounding factors, causal inferences cannot be established. Further prospective studies are warranted to evaluate the role of TPE and optimize patient selection.
2026-06-21 | Chimeric antigen receptor-based cell therapies for neuroimmune disorders: Therapeutic advances and structured standard treatment models.
Chimeric antigen receptor-engineered cell therapies provide a novel therapeutic approach for refractory neuroimmune disorders. These cell products penetrate deep into tissue and achieve long-term depletion of pathogenic B cells and plasma cells, supporting sustained immune tolerance and durable clinical remission. Chimeric antigen receptor-T cells, chimeric antigen receptor-natural killer cells, chimeric autoantigen receptor T cells, and chimeric antigen receptor-regulatory T cells selectively target and eliminate pathological immune effectors, reduce autoantibody levels, and help maintain long-term remission in multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disorder, chronic inflammatory demyelinating polyneuropathy, and autoimmune encephalitis. This review summarizes the therapeutic advance of chimeric antigen receptor-based cell therapies for neuroimmune disorders. Growing clinical evidence indicates that CD19-directed and B-cell maturation antigen-directed chimeric antigen receptor-T cells provide rapid and persistent clinical improvement even in patients with multiple prior treatment failures, accompanied by depletion of the B-cell lineage and sustained reduction in autoantibody titers. Key mechanisms include enhanced access across the blood-brain barrier, targeted lysis of tissue-resident memory B cells and long-lived plasma cells, and subsequent immune repertoire reconstitution. Important challenges remain incompletely defined, including long-term safety, late relapse, high manufacturing expenses, and restricted availability of autologous cell products. Further advances will require optimized chimeric antigen receptor architectures, off-the-shelf allogeneic platforms, and validation in large controlled clinical trials. This review presents a structured framework for future progress and highlights chimeric antigen receptor based immunotherapy as a pivotal strategy that replaces long term immunosuppression with durable drug free remission, thus reshaping the standard treatment model and redefining therapeutic goals for patients with neuroimmune disorders.
other
2026-08-26 | De-Escalating and Discontinuing Immunotherapies in Patients With NMOSD and MOGAD.
Antibody-mediated inflammatory diseases of the CNS, including aquaporin-4 antibody neuromyelitis optica spectrum disorder (AQP4-Ab NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), have undergone major therapeutic transformation with the advent of sensitive antibody assays and targeted immunotherapies. These advances have markedly reduced relapse rates and improved long-term outcomes. With improved disease control, questions regarding optimal treatment duration and the possibility of de-escalation or discontinuation are increasingly relevant. In AQP4-Ab NMOSD, relapses are typically severe and disabling, and most observational studies show a high risk of reactivation after tapering or withdrawal. Thus, discontinuation is never recommended. Successful de-escalation has been reported in selected patients with prolonged remission, although relapse risk persists, underscoring the need for individualized decisions and close monitoring. In contrast, MOGAD is clinically heterogeneous. Many patients, particularly children, experience a monophasic illness with good recovery, whereas relapse risk in adults appears to decline after several years. De-escalation strategies can thus be applied for anti-CD20 and IVIG. Recent cohort studies suggest that even discontinuation may be feasible after 2 to 5 years of remission in children and adults, especially in those who become seronegative for myelin oligodendrocyte glycoprotein immunoglobulin G. In seronegative NMOSD, the evidence base is limited and prognosis uncertain; attacks can be severe, no therapies are specifically approved, and although some experts suggest that discontinuation may be considered after 5 years of stability, this remains guided by expert opinion alone. Treatment de-escalation is sometimes necessary because of adverse effects, comorbidities, infections, treatment fatigue, or life circumstances such as pregnancy. In pregnancy, management requires balancing maternal disease control with fetal safety, with strategies ranging from continuation of selected therapies to temporary tapering or deferral. Monitoring with MRI, OCT, and emerging fluid biomarkers offers potential to detect early recurrence of disease activity, although none are validated for routine use. Prospective studies, real-world registry data, and dedicated trials are urgently needed to inform safe and patient-centered de-escalation/discontinuation strategies.
2026-06-08 | Synergistic Interaction Between MALAT1/miR-30b-5p/BAFF Axis and Inflammatory Cytokines Underlies Rituximab-Refractory NMOSD.
Despite achieving complete peripheral B cell deletion after over 6 months of rituximab therapy, a clinically significant minority of neuromyelitis optica spectrum disorder (NMOSD) patients experience breakthrough relapses, yet the underlying mechanism remains unclear. Our study aims to explore the underlying mechanism-the contribution of the MALAT1/miR-30b-5p/BAFF axis activation in monocytes to NMOSD disease attacks and relapses resistant to rituximab therapy. To investigate immune dysregulation in NMOSD, we established clinical groups comprising peripheral blood mononuclear cells (PBMCs) and serum from NMOSD patients: onset cases (PBMCs: n = 10; serum: n = 23) and rituximab-treated cases subdivided into remission (n = 26) and rituximab-refractory relapse (n = 13), along with healthy controls (n = 15). To profile the MALAT1/miR-30b-5p/BAFF axis and inflammatory mediators, we quantified MALAT1, miR-30b-5p, BAFF, and cytokine levels using qPCR, ELISA, and Western Blot and validated molecular interactions via dual-luciferase reporter assays. To characterize cellular heterogeneity, single-cell RNA sequencing (scRNA-seq) was performed on PBMCs from two rituximab-refractory relapsed NMOSD patients, two rituximab-remission NMOSD patients, and two healthy controls. For mechanistic validation, THP-1 cells were transfected with MALAT1 overexpression constructs or miR-30b-5p mimics, followed by functional assessments to determine their roles in monocyte activation and cytokine production. Significant activation of the MALAT1/miR-30b-5p/BAFF axis was observed in NMOSD patients at disease onset compared to healthy controls. Moreover, this axis correlated with rituximab-refractory NMOSD, featuring monocyte-specific MALAT1 upregulation and elevated serum BAFF in rituximab-refractory relapse patients. In THP-1 cells, the overexpression of MALAT1 downregulated miR-30b-5p, resulting in increased BAFF expression and pro-inflammatory cytokines secretion (IL-1β, IL-8, TNF-α), while also accelerating cell proliferation. Significantly, transfection with miR-30b-5p mimics reversed the MALAT1-driven upregulation of BAFF and pro-inflammatory cytokines, supporting the MALAT1/miR-30b-5p/BAFF axis as a regulatory circuit underlying inflammatory dysregulation in NMOSD. We identify the MALAT1/miR-30b-5p axis as a driver of NMOSD pathogenesis and rituximab-refractory relapse. Upregulation of monocytic MALAT1 suppresses miR-30b-5p, leading to increased BAFF and pro-inflammatory cytokines secretion, thereby promoting inflammatory responses. Targeting this pathway may offer therapeutic potential for relapse prevention.
2025-09-20 | CRISPR and Myelin regeneration: a systematic review of applications in demyelinating CNS Disorders, with a focus on MS.
Current treatments for demyelinating disorders focus on slowing progression but fail to repair damaged myelin. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) -based technology has the potential to address key challenges in myelin repair by targeting genetic dysfunctions, modulating immune responses, and promoting oligodendrocyte differentiation. This systematic review aimed to evaluate CRISPR applications for myelin regeneration. A comprehensive search of PubMed, Scopus, and other databases identified 48 studies. The included studies employed CRISPR in diverse experimental models, targeting genes associated with immune regulation and astrocyte activity, as well as correcting RNA splicing dysfunctions linked to neurodegeneration. CRISPR-edited stem cells showed significant potential in promoting myelin regeneration, with enhanced functional recovery in animal models of multiple sclerosis (MS). While most research focused on MS, promising applications were also observed in neuromyelitis optica spectrum disorder (NMOSD), such as reducing astrocytic damage via AQP4 targeting, and in progressive multifocal leukoencephalopathy (PML), where CRISPR disrupted JC polyomavirus replication. Despite its promise, challenges remain. Future research should prioritize optimizing CRISPR delivery systems, expanding applications to underexplored disorders, and conducting long-term safety assessments. Early results are encouraging, but further studies are essential to translate preclinical success into clinical therapies.
2025-08-11 | Glial-mediated pathogenesis and intervention strategies in neuromyelitis optica spectrum disorder.
Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune disease primarily characterized by anti-aquaporin-4 immunoglobulin G (AQP4-IgG)-mediated astrocyte injury, neuroinflammation, and demyelination. Glial cells-including astrocytes, microglia, and oligodendrocyte lineage cells-play central roles in NMOSD pathogenesis. Astrocyte loss induced by AQP4-IgG initiates a cascade of immune responses involving microglial activation, proinflammatory cytokine release, and subsequent oligodendrocyte damage. Activated microglia further exacerbate inflammation and tissue injury, while oligodendrocyte dysfunction impairs remyelination. This review summarizes the region-specific distribution and pathological functions of glial cells in NMOSD and highlights their contributions to both lesion formation and repair processes. We also discuss current and emerging therapeutic strategies targeting glial dysfunction, including IL-6 receptor inhibitors, complement blockers, BTK inhibitors, hiPSC-derived glial cell therapies, and microglia-derived exosomes. Understanding the dual roles of glial cells in mediating neuroinflammation and promoting repair offers new insights into disease mechanisms and supports the development of glia-targeted interventions in NMOSD.
2025-08-11 | Pediatric-Onset Neuromyelitis Optica Spectrum Disorder in Isfahan: Insights from a Cross-Sectional Study.
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune demyelinating disease of the central nervous system. While NMOSD predominantly affects adults, pediatric-onset NMOSD (PONMOSD) cases are increasingly recognized, necessitating a better understanding of the disease in this population. This study aims to provide a comprehensive insight into the manifestations and management of PONMOSD. This study was conducted at the Isfahan MS Clinic, Iran, recruiting 182 NMOSD patients between March 2021 and March 2022. Board-certified neurologists performed diagnosis and examination, applying the 2015 NMOSD diagnostic criteria. Clinical data were collected and analyzed, including demographic information, onset symptoms, family history, treatment, and MRI findings. Eighteen patients with PONMOSD (9.9% of the total) were identified. The study cohort had a female-to-male ratio 2.6:1, with the most common onset symptoms being optic neuritis (ON) and transverse myelitis (TM). AQP4-Ab was positive in 66.7% of the patients, with longitudinally extensive transverse myelitis (LETM) being the most common MRI finding. Azathioprine and Rituximab were the most commonly used treatments in patients, respectively. Treatment response was generally favorable, with most patients responding to therapy. The present study provides valuable insights into the clinical characteristics and management of pediatric-onset NMOSD. Despite challenges in diagnosis and treatment, early recognition and appropriate management strategies can lead to improved outcomes in this population. Further research is needed to optimize diagnostic criteria and therapeutic approaches for pediatric NMOSD.
small molecules
2026-09-29 | Case Report: Confirmed and suspected heparin-induced thrombocytopenia during therapeutic plasma exchange in neuromyelitis optica spectrum disorder: a single-centre case series.
Neuromyelitis optica spectrum disorder (NMOSD) is a B-cell-mediated autoimmune disease associated with aquaporin-4 (AQP4-IgG) antibodies in which patients may require anticoagulation, including heparin for venous thromboembolism prophylaxis, thereby exposing them to a risk of heparin-induced thrombocytopenia (HIT), an immune-mediated complication caused by antibodies directed against PF4-heparin complexes. Whether anti-AQP4-mediated autoimmunity contributes to susceptibility to anti-PF4/heparin immune responses warrants further investigation. Four cases of suspected or confirmed HIT in patients with NMOSD are presented, together with a review of the current literature. In our NMOSD cohort (n=90), 24 patients underwent therapeutic plasma exchange (TPE), among whom HIT was suspected in four cases (16,7% suspected and 8.3% immunoassay positive). These findings underscore the need for vigilance regarding HIT and thromboembolic complications in NMOSD patients undergoing relapse treatment with TPE. Strategies for the safe continuation of TPE using non-heparin anticoagulation and considerations for outpatient management are also addressed. Awareness of this potential association may facilitate earlier recognition and appropriate management in clinical practice.
2026-09-29 | Metabolic reprogramming in neuromyelitis optica spectrum disorder: From astrocyte dysfunction to immune-mediated neuroinflammation.
Neuromyelitis optica spectrum disorders comprise a group of autoimmune diseases of the central nervous system, defined primarily by astrocyte injury mediated by anti-aquaporin-4 antibodies. Although targeted therapies directed against B cells, complement, and inflammatory mediators have substantially reduced the relapse risk in recent years, a subset of patients still exhibits persistent neurological impairment. Recent advances in immunometabolic research suggest that metabolic reprogramming may be a potentially important regulatory process linking immune abnormalities to neurological damage.This review synthesizes the current understanding of metabolic abnormalities and their underlying mechanisms in NMOSD from an immunometabolic perspective, with a particular focus on the interplay between astrocyte damage and disruption of metabolic homeostasis. Current research suggests that AQP4-IgG-mediated astrocyte dysfunction may disrupt the metabolic support network of the central nervous system, which in turn may lead to energy metabolism disorders and mitochondrial dysfunction, and further affect the metabolic state of immune cells. Metabolically reprogrammed T cells and B cells may exhibit functional shifts, which could contribute to the persistence of inflammation and the progression of tissue damage.Among these, metabolic regulatory pathways, including mTOR, AMPK, and HIF-1α, appear to participate in metabolic adaptation and immune regulation across various cell types. Based on these findings, targeting the regulatory networks of glycolysis, mitochondrial homeostasis, and immunometabolic regulation may offer new therapeutic approaches for NMOSD; however, most intervention strategies are still in the experimental exploration phase.Research into metabolic reprogramming in NMOSD remains in its nascent stages. Future investigations, integrating multi-omics approaches and relevant disease models, will be essential to further identify key metabolic targets and to explore the potential synergy between metabolic interventions and existing immunotherapies.
2026-09-22 | Micheliolide and ACT001 as Covalent Modulators of Inflammation-Redox-Metabolism Networks in CNS Disorders: An Evidence-Stratified Review of Mechanisms and Translational Challenges.
Micheliolide (MCL), a guaianolide sesquiterpene lactone bearing an α-methylene-γ-lactone Michael acceptor pharmacophore, and its orally bioavailable prodrug ACT001 have been studied in a growing range of central nervous system (CNS) disorders, including traumatic brain injury, Parkinson's disease, neuropathic pain, neuromyelitis optica spectrum disorder, and glioblastoma. These compounds act beyond classical pathway inhibition (that is, blockade of any single linear signalling cascade in isolation) by modulating interconnected inflammatory, redox, and metabolic signalling modules. This review integrates preclinical evidence across CNS disease models and proposes a unified three-axis framework-encompassing innate immune-inflammatory regulation, redox homeostasis, and metabolism-associated signal integration-to organise mechanistic findings, stratify evidence by direct CNS validation status, and identify translational gaps. This review is based on a structured search of PubMed and Web of Science for publications on micheliolide, DMAMCL, or ACT001 in central nervous system disorders, and the diseases are discussed in the sequence in which the supporting evidence is presented below. The inflammatory axis (NF-κB/NLRP3/TLR4/MD2/STAT3) is the best-supported CNS-relevant mechanism, with convergent evidence across traumatic brain injury, Parkinson's disease, neuropathic pain, and glioblastoma, including direct binding to the TLR4 co-receptor MD2 and IKKβ. Redox modulation (KEAP1/NRF2) remains plausible but rests primarily on peripheral models, awaiting CNS validation. The metabolism-associated axis (PKM2, GAPDH, MDK/c-Myc) is an innovative but incompletely validated frontier, with GAPDH Cys247 covalent engagement in glioblastoma as the strongest direct CNS evidence. We propose a disease-stratified model-neurodegeneration as inflammation-dominant, acute brain injury as inflammation-metabolism coupled, autoimmune and pain conditions as glial-lineage-expanded, and brain tumours as multi-axis dysregulated-requiring experimental validation. Although glioblastoma is the most translationally advanced indication for this chemotype, the shared neuroinflammatory, redox, and metabolic mechanisms engaged by MCL/ACT001 provide a strong rationale for their evaluation across non-malignant CNS disorders. MCL and ACT001 represent a promising covalent scaffold for modulating interconnected CNS networks, with glioblastoma as the most translationally advanced indication. Priorities include quantitative CNS pharmacokinetics, long-term safety of covalent pharmacology in post-mitotic neurons, and validation of metabolic-redox coupling in brain-resident cells via chemoproteomic and single-cell approaches.
2026-09-20 | Potential links between gut microbiota-derived propionate and succinate and CXCL8, IL1B, and IL6 in NMOSD: An integrated network pharmacology and mendelian randomization study.
Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune demyelinating disease of the central nervous system. Gut microbiota metabolites may participate in NMOSD pathogenesis, but their biological relevance and underlying molecular links remain unclear. Candidate key targets of gut microbiota metabolites in NMOSD were obtained from the intersection of public database targets (human gut, NMOSD, and metabolite targets). Functional enrichment and regulatory network analyses were conducted. Microbiota-metabolite-target-signaling pathway (MMTS) network, Mendelian randomization (MR) analysis, and metabolite evaluations (drug-likeness, toxicology, and molecular docking) were performed. CXCL8, IL1B, and IL6 were identified as candidate key targets. Notably, they were enriched in pathways related to immune regulation and inflammatory responses, such as "NOD-like receptor signaling pathway", "Toll-like receptor signaling pathway", and "IL-17 signaling pathway". Predicted regulatory factors included hsa-miR-191-5p and hsa-let-7c-5p. Additionally, Barnesiella intestinihominis, Ruminococcus bromii, and Ruminococcus champanellensis were identified as key microbiota. Their associated key metabolites, including propionate and succinate, exhibited favorable drug-likeness, low toxicity, and promising binding affinities to the candidate key targets. This study suggests that gut microbiota metabolites may affect NMOSD through CXCL8, IL1B, IL6, and immune-inflammatory pathways. Propionate and succinate were identified as candidate metabolites requiring experimental validation of their effects on these targets.
2026-09-03 | The cGAS-STING Pathway: A Double-Edged Regulator of Neuroinflammation and Myelin Regeneration.
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA sensor that mediates innate immunity by inducing type I interferons (IFN-I) and proinflammatory cytokines. Although its role in antiviral defense and tumor immunity has been well established, emerging evidence suggests that it is also closely involved in demyelinating diseases of both the central and peripheral nervous systems (PNS). Such diseases, exemplified by multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), are characterized by immune-mediated inflammation, oxidative stress, mitochondrial dysfunction, and impaired myelin regeneration. This review systematically examines the diverse roles of the cGAS-STING pathway in demyelination. We summarize how moderate activation of this pathway promotes protective inflammation and autophagy, facilitating debris clearance and supporting remyelination during the early stages of disease. In contrast, excessive or sustained activation exacerbates neuroinflammation, hinders remyelination, and promotes progressive axonal injury. The involvement of cGAS-STING in T cell polarization, reactive oxygen species (ROS)-mediated injury, and antiviral responses further underscores its dual role in both disease initiation and progression. Understanding the context-dependent effects of cGAS-STING signaling in demyelinating diseases offers valuable insights for developing targeted therapeutic strategies. However, this review also emphasizes that most current evidence is derived from cellular and animal models. Given that the effects of cGAS-STING signaling are highly context dependent and may vary among different demyelinating diseases, disease stages, and cell types, further clinically relevant studies are required to validate its therapeutic potential.
antibodies
2026-09-30 | Optimizing the management of AQP4 antibody-positive NMOSD: A Canadian consensus.
Aquaporin-4-IgG-positive (AQP4+) neuromyelitis optica spectrum disease (NMOSD) is a rare demyelinating disorder/astrocytopathy with an estimated prevalence of 1 per 100,000 population in Canada. An expert panel of Canadian clinicians developed consensus recommendations for the diagnosis and treatment of AQP4+ NMOSD to optimize patient outcomes. Panel co-chairs (DLR, MSF) developed recommendations for voting by the 18 consensus group members using a modified e-Delphi method. Statements with an average >4.25 on a 5-point Likert-type scale were adopted. Consensus was achieved for 25 of 27 recommendations on the first round of voting; two recommendations achieved consensus after revision with a second round of voting. There was consensus on the application of current international criteria for the diagnosis of AQP4+ NMOSD in pediatric and adult patients; use of a live or fixed cell-based assay to detect AQP4 antibodies; urgent early use of intravenous methylprednisolone and plasma exchange for acute attacks; use of a prednisone taper until dosing of a maintenance therapy is optimized; and initiation of long-term maintenance therapy with a monoclonal antibody therapy. It was recommended that vaccination status be checked and vaccinations updated, including administration of any missing non-live vaccinations in patients on prednisone following a relapse. There was consensus that treatment should be maintained long-term since discontinuation is associated with considerable risk of potentially disabling relapses regardless of age and/or disease stability. It is hoped that this expert consensus will help guide the management of AQP4+ NMOSD patients and improve long-term outcomes.
2026-09-29 | Diagnostic delay and poor functional outcomes in late-onset NMOSD: A Thai cohort study.
Late-onset neuromyelitis optica spectrum disorder (LONMOSD) may be difficult to recognize because symptoms can mimic other neurological disorders in older patients. Data on LONMOSD in Thailand remain limited. To compare clinical characteristics and outcomes between early-onset NMOSD (EONMOSD) and LONMOSD in a Thai cohort, and to evaluate the impact and causes of delayed diagnosis in LONMOSD. We retrospectively studied adult patients with NMOSD who fulfilled the 2015 International Panel for NMO Diagnosis criteria at a tertiary referral center in Thailand from 2016 to 2025. LONMOSD was defined as onset at age ≥50 years. Clinical characteristics, treatment, Expanded Disability Status Scale (EDSS), relapse outcomes, and reasons for delayed diagnosis were analyzed. Among 148 patients, 91 had EONMOSD and 57 had LONMOSD. LONMOSD was associated with more frequent delayed diagnosis than EONMOSD (54.4%vs 31.9%, P = 0.01). LONMOSD patients had higher EDSS at nadir, 90 days, and 180 days, and lower recovery index at 180 days. Relapse outcomes and time to subsequent relapse were not significantly different between groups. In LONMOSD, myelitis was independently associated with EDSS ≥6 at 90 and 180 days, while delayed diagnosis was associated with EDSS ≥6 at 90 days. Misdiagnosis was the main cause of delayed diagnosis, most commonly cerebrovascular disease and compressive myelopathy. LONMOSD was associated with delayed diagnosis and worse functional outcomes. Early recognition may reduce preventable disability in older patients.
2026-09-12 | Recognition and management of acute relapse of multiple sclerosis, neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease.
Autoimmune diseases of the central nervous system include multiple sclerosis (MS) and an ever-expanding spectrum of related disorders, such as neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Despite differences in targeted neuroantigens and immune effector mechanisms, these disorders share a common clinical pattern: acute neurological episodes, typically termed attacks at the onset, and relapses during the disease course. Timely recognition of an acute attack or relapse is challenging, not only because of discrepancies between patient-reported and physician-affirmed neurological symptoms, but also due to other confounding factors, such as comorbidities, treatment-related side effects, and transient symptom fluctuations unrelated to underlying disease. Once an attack/relapse is recognized, prompt initiation of treatment is essential, as responsiveness to treatment at the acute stage largely determines the long-term neurological outcomes. In this review, we focus on MS, NMOSD and MOGAD, and discuss the clinical patterns of acute attacks and relapses, including the clinical and para-clinical modalities that are critical for timely recognition and diagnosis. We present the available evidence regarding treatment selection and responsiveness for three categories of therapy: intravenous methylprednisolone (IVMP), intravenous immunoglobulin (IVIG), and plasma exchange/immunoadsorption (PLEX/IA). Notably, we update ongoing clinical trials that incorporate fast-acting, targeted biologic complement inhibitors and neonatal Fc receptor (FcRn) antagonists. We discuss potential drivers of relapses and emerging mechanism-guided interventions for acute management. Finally, we call for international collaborative efforts in this important yet under-investigated area to establish clear criteria for relapse, with the ultimate goal of developing more effective therapies.
2026-09-09 | Right Knee Ureaplasma Septic Arthritis in an Immunocompromised Host, Requiring Right Hip Disarticulation for Definitive Source Control.
Ureaplasma urealyticum is a fastidious, urease-producing bacterium typically responsible for urogenital infections. In immunocompromised hosts, a full-thickness mucosal breach may be complicated by hematogenous spread, leading to septic arthritis in distant joints U. urealyticum is difficult to isolate on routine culture and requires special media or 16S rRNA polymerase chain reaction for detection. We report a 26-year-old immunocompromised female with neuromyelitis optica on long-term cyclosporine and Grave's disease, who developed chronic right knee U. urealyticum septic arthritis. She presented with the right calf pain; knee aspiration was turbid but culture-negative on routine testing. Despite 6 weeks of empirical antibiotics, symptoms persisted, and arthroscopic biopsy with 16S molecular testing eventually identified U. urealyticum. She was treated with multiple antibiotic regimens, including intravenous (IV) aztreonam, vancomycin, oral levofloxacin, and IV azithromycin, and her immunosuppression was reduced. Despite this, she developed medial tibial plateau osteomyelitis, an intra-articular abscess, and a sinus tract, requiring multiple debridements, cement spacer insertion, external fixation, and eventually two-stage revision knee replacement with flap reconstruction. Cultures remained persistently positive for U. urealyticum despite prolonged therapy and repeated surgery. One year after the index revision attempt, she underwent above-knee amputation for source control, followed by hip disarticulation 1 month later due to persistent stump infection. With aggressive wound care, including negative pressure wound therapy and staged dressing de-escalation, the wound achieved complete healing. She was discharged 180 days after hip disarticulation and, at 2-year follow-up, was ambulant with a hip prosthesis, independent in activities of daily living, and had returned to work. This case highlights the diagnostic challenge and potential severity of U. urealyticum septic arthritis in immunocompromised hosts, which may progress to refractory osteomyelitis and necessitate radical surgical measures, including amputation, for definitive source control despite prolonged targeted antibiotic therapy.
2026-09-02 | HLA polymorphism in neuroimmune diseases: linking antigen presentation to neuroinflammatory programs.
Human leukocyte antigen (HLA) polymorphism shapes antigen presentation and susceptibility to immune-mediated disease. In neuroimmune disorders, a central question is how HLA-dependent antigen visibility becomes disease-specific immunity and tissue injury. In this Review, we integrate genetic, molecular, cellular, and clinical evidence across multiple sclerosis (MS), neuromyelitis optica spectrum disorder, Guillain-Barré syndrome, narcolepsy, autoimmune encephalitis, and myasthenia gravis. The HLA-DR15-MS axis is the most mechanistically resolved example, linking allele-specific peptide display to autoreactive T-cell repertoires and convergent Epstein-Barr virus-related immune pathways. In other disorders, this upstream principle operates through distinct effectors, target tissues, molecular subtypes, and ancestral contexts, while causal peptide-receptor complexes often remain unresolved. We therefore separate association strength from mechanistic resolution and position glial activation and tissue injury mainly as downstream, context-dependent processes. This evidence-bounded synthesis identifies where HLA mechanisms are established, suggestive, or still inferred from association.
proteins
2026-08-08 | Complement C3 inhibitory peptide AMY-101 ameliorates brain injury in a mouse model of NMOSD.
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory demyelinating disease of the central nervous system, clinically characterized primarily by optic neuritis and transverse myelitis. This study aimed to investigate the therapeutic potential of the complement C3 inhibitory peptide AMY-101 in experimental models of NMOSD. In vitro experiments were performed using AQP4-transfected cells exposed to AQP4-IgG and human complement to assess complement-dependent cytotoxicity and membrane attack complex (MAC) deposition. In vivo efficacy was evaluated in an intracerebral injection mouse model of NMOSD, in which histopathological changes after AMY-101 treatment were compared with those in untreated controls. AMY-101 significantly attenuated AQP4-IgG- and complement-mediated cytotoxicity and inhibited MAC formation in vitro. In the NMOSD mouse model, AMY-101 treatment markedly reduced astrocyte loss, AQP4 depletion, and demyelination compared with controls. These findings demonstrate that complement C3 inhibition with AMY-101 effectively ameliorates key pathological features of NMOSD in experimental models, supporting its potential as a therapeutic strategy and providing a rationale for further preclinical and clinical investigation.
2026-07-15 | Ferritin-ApoE nanocarrier for targeted therapy of neuromyelitis optica spectrum disorder in mice.
Neuromyelitis optica spectrum disorder (NMOSD) is a chronic inflammatory autoimmune disease affecting the central nervous system (CNS), characterized by anti-aquaporin 4 (AQP4) antibody-mediated damage to astrocytes, resulting in subsequent demyelination. Our prior work identified the protective effects of the apolipoprotein E130-149 (ApoE130-149) peptide in NMOSD mice by promoting astrocyte-microglia intercellular communication. However, its therapeutic potential is restricted due to the limited penetration of the blood-brain barrier (BBB) with systemic administration. Here, we designed a heavy-chain ferritin (HFn)-based nanocarrier containing the ApoE130-149 peptide (HFn-ApoE130-149), specifically engineered for CNS delivery. HFn-ApoE130-149 was constructed through genetic engineering by fusing the coding sequence of HFn with that of the ApoE130-149 peptide in a recombinant plasmid. An acute NMOSD mouse model was induced by transcranial co-injection of AQP4-IgG and human complement (hC) into the brain. The distribution of Cy5.5-labeled HFn-ApoE130-149 post intravenous injection was tracked using in vivo fluorescence imaging to confirm its presence in the brain and peripheral organs. Lesions in the brain were quantified using T2-weighted 7 Tesla magnetic resonance imaging (7T-MRI). Neuropathological features of NMOSD were evaluated by immunostaining of brain sections. Neuroinflammation and immune cell infiltration were analyzed via flow cytometry. The key signaling pathways regulated by HFn-ApoE130-149 were investigated through Western blot (WB) analysis. The interaction between HFn-ApoE130-149 and its receptors was validated through co-immunoprecipitation and visualized on microglia using proximity ligation assay (PLA). Finally, the therapeutic effect on spatial learning and memory was evaluated using the Morris water maze (MWM) test. The HFn-ApoE130-149 effectively crossed the BBB, attenuated lesion progression and demyelination, as well as preserved AQP4 expression and astrocytic integrity in NMOSD mice. The treatment induced a spatial and phenotypic restructuring of the astrocytic response, notably reducing excessive astrocyte accumulation around lesions while encouraging a proliferative and reparative phenotype. Furthermore, HFn-ApoE130-149 influenced microglial polarization towards an anti-inflammatory state, reducing infiltration of peripheral immune cells. Mechanistically, HFn-ApoE130-149 exerted its anti-inflammatory effects through the low-density lipoprotein receptor-related protein 1 (LRP1) -nuclear factor kappa B (NF-κB) signaling axis in microglia. Functional binding of HFn-ApoE130-149 to LRP1 suppressed inhibitor of NF-κB (IκBα) phosphorylation, thereby inhibiting NF-κB nuclear translocation and the subsequent release of pro-inflammatory cytokines, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Knocking down LRP1 reversed these effects, highlighting the importance of the LRP1-NF-κB signaling axis in the nanotherapeutic's efficacy. Treatment with HFn-ApoE130-149 improved spatial learning and rescued memory deficits in NMOSD mice. This study demonstrates that the engineered nanodrug HFn-ApoE130-149 is a promising targeted therapy for alleviating NMOSD pathology by enhancing BBB penetration and suppressing neuroinflammation through the LRP1-NF-κB signaling axis.
2026-02-13 | Therapeutic immune tolerance for central nervous system autoimmune diseases - Prospects, challenges and pitfalls.
Autoimmune diseases of the central nervous system (CNS), including multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), are characterized by chronic inflammation driven by autoreactive immune responses against CNS antigens. Successes in the development of efficacious immunotherapies are hampered by the risks of broad immunosuppression and the consequences of compromising physiological immune functions. Antigen-specific immune tolerance offers a promising alternative by selectively silencing pathogenic immune responses while preserving global immune competence. Advances in understanding of pathophysiology and target antigens in multiple sclerosis, neuromyleitis optica spectrum disroders (NMOSD) myelin oligondendrocyte protein (MOG) antibody associated disease (MOGAD) have enabled the development of antigen-based tolerization strategies. These approaches primarily act through restoration of peripheral tolerance via modulation of autoreactive T and B cell responses. Clinical trials in MS and NMOSD have provided critical insights into key challenges of translation and clinical development, including optimal antigen selection, route of administration, patient stratification and trial design constraints. Future progress in MS, NMO and MOGAD will also depend on precise characterization of immunodominant epitopes and the development of standardized biomarkers of tolerance induction and their integration in novel trial designs. Successful induction of durable, antigen-specific immune tolerance would represent a paradigm shift in treating CNS autoimmunity, enabling disease-specific, safe, and sustained remission without generalized immunosuppression.
2026-01-28 | Therapeutic effects of IGF-2 on NMOSD by inhibiting astrocyte apoptosis through modulation of the IGF-1R/PI3K/AKT signaling pathway.
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease characterized by the presence of antibodies specific to the aquaporins 4 (AQP4) protein. The complexity of its pathogenesis poses significant challenges to treatment, which remains both limited and costly. Consequently, there is an urgent need to elucidate the pathogenesis of NMOSD and to develop novel therapeutic strategies. Here, through a proteomic screen of serum from AQP4-IgG-positive NMOSD patients and a control cohort, we observed a significant downregulation of Insulin-like growth factor 2 (IGF-2) in the serum of AQP4-IgG-positive NMOSD patients and correlated with disease severity. Injecting adenovirus overexpressing IGF-2 into the brains of NMOSD mice reduced microglia, neuroinflammation, and brain injury. Both in vivo and in vitro experiments show IGF-2 activates the IGF-1R/PI3K/AKT pathway, reducing apoptosis and inflammation. These findings highlight IGF-2 as a promising target for NMOSD diagnosis and treatment, offering new insights into disease mechanisms and potential interventions.
2025-10-13 | Size of aquaporin-4 orthogonal arrays of particles are affected by the palmitoylation state of the M1 isoform.
Human aquaporin-4 (AQP4) is a water-channel protein crucial for water-ion homeostasis in the central nervous system. Dysregulation of AQP4 function is linked to neurological conditions like brain edema, neuromyelitis optica, and epilepsy. AQP4 has two isoforms, M1 and M23. The M23 isoform forms large structures known as Orthogonal Arrays of Particles (OAPs), while M1 coats the outer surface of OAPs. The dynamics of OAP aggregation may modulate water permeability and ion homeostasis in the brain. This study shows that the palmitoylation state of M1 influences OAP self-assembly, with depalmitoylated M1 producing OAPs 20 % larger than those formed by palmitoylated M1 at the same concentration. This, along with prior research on M1 aggregation, suggests palmitoylated M1 forms a single outer layer arounf OPAs, whereas depalmitoylated M1 creates a double layer. Single-particle tracking was used to study M23 OAP formation in lipid bilayers under equilibrium conditions. Our data support the idea that M1 regulates M23 OAP size, showing that average OAP size decreases as M1 concentration increases. This study explores the inhibitory effects of M1 on AQP4 M23 assembly and how M1's palmitoylation state affects OAP size regulation. These insights could lead to new therapeutic approaches for managing AQP4 assembly and function in related conditions.
cell therapies
2026-09-25 | Stem Cell-Based Therapies for Central Nervous System Demyelinating Diseases: Clinical Evidence, Therapeutic Niches, and Translational Boundaries.
Central nervous system demyelinating disorders differ substantially in pathobiology, reversibility, and capacity for tissue repair. Disease-modifying therapies can suppress inflammatory activity in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), but they do not replace lost oligodendrocytes or reliably reverse established neuroaxonal injury. Stem cell-based strategies therefore pursue distinct therapeutic goals, including immune reconstitution, paracrine immunomodulation and neuroprotection, direct cell replacement, remyelination, and correction of defined genetic defects. Autologous hematopoietic stem cell transplantation (AHSCT) currently has the most mature clinical evidence, particularly for carefully selected patients with highly active relapsing MS despite high-efficacy therapy, but its benefit is mediated primarily through immune ablation and reconstitution rather than direct remyelination. Mesenchymal stromal cell (MSC) approaches remain investigational because controlled trials have not established consistent efficacy and intrathecal delivery has raised route-specific safety concerns. MSC-derived extracellular vesicles and induced pluripotent stem cell (iPSC)-derived oligodendrocyte or neural progenitor products remain preclinical or early translational approaches for acquired demyelinating disease, whereas gene-modified hematopoietic stem cells have a distinct role in selected inherited leukodystrophies. Translation across these platforms is additionally constrained by product heterogeneity, potency assessment, manufacturing reproducibility, long-term safety, regulation, scalability, access, and the need for mechanism-matched clinical endpoints. This article aims to critically review the clinical evidence, therapeutic niches, safety considerations, and translational boundaries of stem cell-based therapies for central nervous system demyelinating diseases, with particular emphasis on MS and NMOSD.
2026-09-16 | Regulatory T cells as drivers of CNS remyelination: neuro-immune cross-talk and comparative insights from mammalian and zebrafish models.
Demyelination of the Central Nervous System (CNS) is a pathological process that causes the destruction of the myelin sheath, the insulating cover that protects the nerve fibres. This serves as one of the major attributes of numerous neurological disorders, such as Multiple Sclerosis (MS), Neuromyelitis Optica Spectrum Disorder (NMOSD), Acute Disseminated Encephalomyelitis (ADEM), Myelin Oligodendrocyte Glycoprotein-related antibody disease (MOGAD), etc. It is usually initiated as an immune-mediated injury to myelin, followed by dysregulation of the immune system and ultimately failure of effective remyelination. Although oligodendrocytes in the CNS have some capacity for regeneration, the surrounding microenvironment severely inhibits their function, which results in a reduced regenerative outcome. Previously referred to as suppressor T cells, regulatory T cells (Tregs) are a subset of T cells that were traditionally thought to have an immunosuppressive function. However, it has just recently been shown that they directly contribute to regeneration and repair. The goal of this review is to demonstrate how Tregs can promote regeneration by balancing a variety of underlying molecular and cellular processes. Recent research shows that Tregs affect oligodendrocyte lineage progression, microglial and astrocytic responses, and the milieu around the demyelination site in order to perform remyelination. These effects are age-dependent and occur both temporally and geographically. In order to offer an evolutionary perspective on the conserved immune-mediated regenerative pathways that may be diminished in mammals and can be further investigated for therapeutic purposes, this review also aims to draw comparisons between the mechanisms used by regeneration-competent and non-competent species.
2026-08-18 | Therapeutic Plasma Exchange in Neuromyelitis Optica Spectrum Disorder: Real-World Clinical Outcomes and Safety From a Tertiary Care Center in Northwest India.
Neuromyelitis Optica Spectrum Disorder (NMOSD) is a severe autoimmune demyelinating disorder of the central nervous system characterized by relapsing attacks that can result in permanent neurological disability. Therapeutic Plasma Exchange (TPE) is recommended for steroid-refractory acute exacerbations. This study evaluated the efficacy and safety of TPE in patients with acute NMOSD attacks. A prospective observational study was conducted over 18 months at SMS Jaipur, India. Forty adult patients fulfilling the 2015 International Panel for NMO Diagnosis criteria and presenting with steroid-refractory acute attacks were enrolled. TPE was performed using continuous-flow centrifugation, exchanging 1.0-1.4 estimated plasma volumes per session for 3-7 alternate-day procedures. Clinical outcomes were assessed using the EDSS, Snellen visual acuity, and MRC muscle strength grading. The cohort had a female predominance (65.0%) with a mean age of 36.5 years. Acute first presentations accounted for 77.5% of cases, while 22.5% were relapses. Anti-aquaporin-4 antibody positivity was detected in 45.0% of patients. Among 37 patients with motor deficits, 94.6% showed clinical improvement following TPE, including marked (35.1%), moderate (43.2%), and mild (16.2%) responses. Mean EDSS improved significantly from 7.4 to 4.1 (95% CI and p < 0.001). Visual improvement was observed in 84.4% of patients with baseline visual impairment. Adverse events occurred in 25.0% of patients, predominantly transient hypotension and mild citrate-related hypocalcemia, with no procedure-related treatment discontinuation. TPE is a safe and effective rescue therapy for steroid-refractory NMOSD exacerbations, producing substantial neurological and visual recovery with a favorable safety profile.
2026-08-05 | Association of therapeutic plasma exchange with functional outcomes in selected neurological disorders: a retrospective cohort study from a single tertiary center in Saudi Arabia.
Neurological disorders are associated with considerable morbidity and healthcare impact. Therapeutic plasma exchange (TPE) is an intervention that removes pathogenic antibodies, immune complexes, and other plasma constituents from circulation. Previous studies have suggested that TPE could be associated with improved outcomes in selected neurological disorders. To evaluate functional outcomes following therapeutic plasma exchange in patients with selected neurological disorders at National Guard Health Affairs (NGHA) in Jeddah, Saudi Arabia. This retrospective cohort study analyzes 133 patients diagnosed with various neurological disorders who received TPE between August 2015 and December 2022 at NGHA. Diagnoses included multiple sclerosis (MS), myasthenia gravis (MG), Guillain-Barré syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), chronic inflammatory demyelinating polyneuropathy (CIDP), autoimmune encephalitis (AE), and other neurological conditions including amyotrophic lateral sclerosis (ALS), transverse myelitis, cerebellar ataxia, paraneoplastic neurologic syndrome, polymyositis, and central nervous system (CNS) infections. The effectiveness of TPE was assessed using the Modified Rankin Scale (mRS) before and 90 days following the final TPE session. Statistical analysis included Wilcoxon signed-rank tests and Mann-Whitney U test, with significance set at (p < 0.05). Significant improvements in mRS scores were observed following TPE for MS, MG, and GBS (all p < 0.001), as well as for NMOSD (p = 0.008), CIDP (p = 0.007), and AE (p = 0.018), but not in other neurological disorders (p = 0.234). Overall mortality was 6.8%, with no TPE-related deaths. Comorbidities among deceased patients included hypertension, diabetes mellitus, malignancy, chronic kidney disease, and cardiovascular disease. TPE was associated with improved functional outcomes in selected neurological disorders. Comorbidities were common among patients with poorer outcomes. Due to the retrospective design and potential confounding factors, causal inferences cannot be established. Further prospective studies are warranted to evaluate the role of TPE and optimize patient selection.
2026-06-21 | Chimeric antigen receptor-based cell therapies for neuroimmune disorders: Therapeutic advances and structured standard treatment models.
Chimeric antigen receptor-engineered cell therapies provide a novel therapeutic approach for refractory neuroimmune disorders. These cell products penetrate deep into tissue and achieve long-term depletion of pathogenic B cells and plasma cells, supporting sustained immune tolerance and durable clinical remission. Chimeric antigen receptor-T cells, chimeric antigen receptor-natural killer cells, chimeric autoantigen receptor T cells, and chimeric antigen receptor-regulatory T cells selectively target and eliminate pathological immune effectors, reduce autoantibody levels, and help maintain long-term remission in multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disorder, chronic inflammatory demyelinating polyneuropathy, and autoimmune encephalitis. This review summarizes the therapeutic advance of chimeric antigen receptor-based cell therapies for neuroimmune disorders. Growing clinical evidence indicates that CD19-directed and B-cell maturation antigen-directed chimeric antigen receptor-T cells provide rapid and persistent clinical improvement even in patients with multiple prior treatment failures, accompanied by depletion of the B-cell lineage and sustained reduction in autoantibody titers. Key mechanisms include enhanced access across the blood-brain barrier, targeted lysis of tissue-resident memory B cells and long-lived plasma cells, and subsequent immune repertoire reconstitution. Important challenges remain incompletely defined, including long-term safety, late relapse, high manufacturing expenses, and restricted availability of autologous cell products. Further advances will require optimized chimeric antigen receptor architectures, off-the-shelf allogeneic platforms, and validation in large controlled clinical trials. This review presents a structured framework for future progress and highlights chimeric antigen receptor based immunotherapy as a pivotal strategy that replaces long term immunosuppression with durable drug free remission, thus reshaping the standard treatment model and redefining therapeutic goals for patients with neuroimmune disorders.
other
2026-08-26 | De-Escalating and Discontinuing Immunotherapies in Patients With NMOSD and MOGAD.
Antibody-mediated inflammatory diseases of the CNS, including aquaporin-4 antibody neuromyelitis optica spectrum disorder (AQP4-Ab NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), have undergone major therapeutic transformation with the advent of sensitive antibody assays and targeted immunotherapies. These advances have markedly reduced relapse rates and improved long-term outcomes. With improved disease control, questions regarding optimal treatment duration and the possibility of de-escalation or discontinuation are increasingly relevant. In AQP4-Ab NMOSD, relapses are typically severe and disabling, and most observational studies show a high risk of reactivation after tapering or withdrawal. Thus, discontinuation is never recommended. Successful de-escalation has been reported in selected patients with prolonged remission, although relapse risk persists, underscoring the need for individualized decisions and close monitoring. In contrast, MOGAD is clinically heterogeneous. Many patients, particularly children, experience a monophasic illness with good recovery, whereas relapse risk in adults appears to decline after several years. De-escalation strategies can thus be applied for anti-CD20 and IVIG. Recent cohort studies suggest that even discontinuation may be feasible after 2 to 5 years of remission in children and adults, especially in those who become seronegative for myelin oligodendrocyte glycoprotein immunoglobulin G. In seronegative NMOSD, the evidence base is limited and prognosis uncertain; attacks can be severe, no therapies are specifically approved, and although some experts suggest that discontinuation may be considered after 5 years of stability, this remains guided by expert opinion alone. Treatment de-escalation is sometimes necessary because of adverse effects, comorbidities, infections, treatment fatigue, or life circumstances such as pregnancy. In pregnancy, management requires balancing maternal disease control with fetal safety, with strategies ranging from continuation of selected therapies to temporary tapering or deferral. Monitoring with MRI, OCT, and emerging fluid biomarkers offers potential to detect early recurrence of disease activity, although none are validated for routine use. Prospective studies, real-world registry data, and dedicated trials are urgently needed to inform safe and patient-centered de-escalation/discontinuation strategies.
2026-06-08 | Synergistic Interaction Between MALAT1/miR-30b-5p/BAFF Axis and Inflammatory Cytokines Underlies Rituximab-Refractory NMOSD.
Despite achieving complete peripheral B cell deletion after over 6 months of rituximab therapy, a clinically significant minority of neuromyelitis optica spectrum disorder (NMOSD) patients experience breakthrough relapses, yet the underlying mechanism remains unclear. Our study aims to explore the underlying mechanism-the contribution of the MALAT1/miR-30b-5p/BAFF axis activation in monocytes to NMOSD disease attacks and relapses resistant to rituximab therapy. To investigate immune dysregulation in NMOSD, we established clinical groups comprising peripheral blood mononuclear cells (PBMCs) and serum from NMOSD patients: onset cases (PBMCs: n = 10; serum: n = 23) and rituximab-treated cases subdivided into remission (n = 26) and rituximab-refractory relapse (n = 13), along with healthy controls (n = 15). To profile the MALAT1/miR-30b-5p/BAFF axis and inflammatory mediators, we quantified MALAT1, miR-30b-5p, BAFF, and cytokine levels using qPCR, ELISA, and Western Blot and validated molecular interactions via dual-luciferase reporter assays. To characterize cellular heterogeneity, single-cell RNA sequencing (scRNA-seq) was performed on PBMCs from two rituximab-refractory relapsed NMOSD patients, two rituximab-remission NMOSD patients, and two healthy controls. For mechanistic validation, THP-1 cells were transfected with MALAT1 overexpression constructs or miR-30b-5p mimics, followed by functional assessments to determine their roles in monocyte activation and cytokine production. Significant activation of the MALAT1/miR-30b-5p/BAFF axis was observed in NMOSD patients at disease onset compared to healthy controls. Moreover, this axis correlated with rituximab-refractory NMOSD, featuring monocyte-specific MALAT1 upregulation and elevated serum BAFF in rituximab-refractory relapse patients. In THP-1 cells, the overexpression of MALAT1 downregulated miR-30b-5p, resulting in increased BAFF expression and pro-inflammatory cytokines secretion (IL-1β, IL-8, TNF-α), while also accelerating cell proliferation. Significantly, transfection with miR-30b-5p mimics reversed the MALAT1-driven upregulation of BAFF and pro-inflammatory cytokines, supporting the MALAT1/miR-30b-5p/BAFF axis as a regulatory circuit underlying inflammatory dysregulation in NMOSD. We identify the MALAT1/miR-30b-5p axis as a driver of NMOSD pathogenesis and rituximab-refractory relapse. Upregulation of monocytic MALAT1 suppresses miR-30b-5p, leading to increased BAFF and pro-inflammatory cytokines secretion, thereby promoting inflammatory responses. Targeting this pathway may offer therapeutic potential for relapse prevention.
2025-09-20 | CRISPR and Myelin regeneration: a systematic review of applications in demyelinating CNS Disorders, with a focus on MS.
Current treatments for demyelinating disorders focus on slowing progression but fail to repair damaged myelin. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) -based technology has the potential to address key challenges in myelin repair by targeting genetic dysfunctions, modulating immune responses, and promoting oligodendrocyte differentiation. This systematic review aimed to evaluate CRISPR applications for myelin regeneration. A comprehensive search of PubMed, Scopus, and other databases identified 48 studies. The included studies employed CRISPR in diverse experimental models, targeting genes associated with immune regulation and astrocyte activity, as well as correcting RNA splicing dysfunctions linked to neurodegeneration. CRISPR-edited stem cells showed significant potential in promoting myelin regeneration, with enhanced functional recovery in animal models of multiple sclerosis (MS). While most research focused on MS, promising applications were also observed in neuromyelitis optica spectrum disorder (NMOSD), such as reducing astrocytic damage via AQP4 targeting, and in progressive multifocal leukoencephalopathy (PML), where CRISPR disrupted JC polyomavirus replication. Despite its promise, challenges remain. Future research should prioritize optimizing CRISPR delivery systems, expanding applications to underexplored disorders, and conducting long-term safety assessments. Early results are encouraging, but further studies are essential to translate preclinical success into clinical therapies.
2025-08-11 | Glial-mediated pathogenesis and intervention strategies in neuromyelitis optica spectrum disorder.
Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune disease primarily characterized by anti-aquaporin-4 immunoglobulin G (AQP4-IgG)-mediated astrocyte injury, neuroinflammation, and demyelination. Glial cells-including astrocytes, microglia, and oligodendrocyte lineage cells-play central roles in NMOSD pathogenesis. Astrocyte loss induced by AQP4-IgG initiates a cascade of immune responses involving microglial activation, proinflammatory cytokine release, and subsequent oligodendrocyte damage. Activated microglia further exacerbate inflammation and tissue injury, while oligodendrocyte dysfunction impairs remyelination. This review summarizes the region-specific distribution and pathological functions of glial cells in NMOSD and highlights their contributions to both lesion formation and repair processes. We also discuss current and emerging therapeutic strategies targeting glial dysfunction, including IL-6 receptor inhibitors, complement blockers, BTK inhibitors, hiPSC-derived glial cell therapies, and microglia-derived exosomes. Understanding the dual roles of glial cells in mediating neuroinflammation and promoting repair offers new insights into disease mechanisms and supports the development of glia-targeted interventions in NMOSD.
2025-08-11 | Pediatric-Onset Neuromyelitis Optica Spectrum Disorder in Isfahan: Insights from a Cross-Sectional Study.
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune demyelinating disease of the central nervous system. While NMOSD predominantly affects adults, pediatric-onset NMOSD (PONMOSD) cases are increasingly recognized, necessitating a better understanding of the disease in this population. This study aims to provide a comprehensive insight into the manifestations and management of PONMOSD. This study was conducted at the Isfahan MS Clinic, Iran, recruiting 182 NMOSD patients between March 2021 and March 2022. Board-certified neurologists performed diagnosis and examination, applying the 2015 NMOSD diagnostic criteria. Clinical data were collected and analyzed, including demographic information, onset symptoms, family history, treatment, and MRI findings. Eighteen patients with PONMOSD (9.9% of the total) were identified. The study cohort had a female-to-male ratio 2.6:1, with the most common onset symptoms being optic neuritis (ON) and transverse myelitis (TM). AQP4-Ab was positive in 66.7% of the patients, with longitudinally extensive transverse myelitis (LETM) being the most common MRI finding. Azathioprine and Rituximab were the most commonly used treatments in patients, respectively. Treatment response was generally favorable, with most patients responding to therapy. The present study provides valuable insights into the clinical characteristics and management of pediatric-onset NMOSD. Despite challenges in diagnosis and treatment, early recognition and appropriate management strategies can lead to improved outcomes in this population. Further research is needed to optimize diagnostic criteria and therapeutic approaches for pediatric NMOSD.
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Drug Discovery Landscape
10 orphan drug designations for Neuromyelitis optica spectrum disorder, including 6 approved therapies.
10 orphan drug designations for Neuromyelitis optica spectrum disorder, including 6 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Edralbrutinib | small molecules | FDA | eVenus Pharmaceutical Lab Inc. | |
Inebilizumab [Uplizna] | antibodies | EMA | Viela Bio B.V. | |
ublituximab | antibodies | FDA | TG Therapeutics, Inc. | |
Humanised anti-IL-6 receptor monoclonal antibody [Enspryng] | antibodies | EMA | Approved | Roche Registration GmbH |
inebilizumab [Uplizna] | antibodies | FDA | Approved | Horizon Therapeutics Ireland DAC |
cladribine | small molecules | FDA | — | Chord Therapeutics S.a.r.l. |
satralizumab-mwge [Enspryng] | antibodies | FDA | Approved | Genentech, Inc. |
Eculizumab [Soliris] | antibodies | EMA | Approved | Alexion Europe SAS |
ravulizumab-cwvz [Ultomiris] | antibodies | FDA | Approved | Alexion Pharmaceuticals, Inc. |
eculizumab [Soliris] | antibodies | FDA | Approved | Alexion Pharmaceuticals, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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