Neurotherapeutics最新文献

{"title":"Nanoparticle and epothilone D combinatorial intervention improves motor performance and regeneration in chronic cervical spinal cord injury.","authors":"Sarah E Hocevar, Brian C Ross, Samantha R Schwartz, Brooke M Smiley, Brian J Cummings, Aileen J Anderson, Lonnie D Shea","doi":"10.1016/j.neurot.2025.e00742","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00742","url":null,"abstract":"<p><p>Spinal cord injury (SCI) causes the loss of motor function below the site of injury due to neuron loss and the severing of spinal tracts. The injury leads to the recruitment of circulating myeloid cells that create an inflammatory microenvironment and exacerbate cell death, with subsequent migration of fibroblasts and astrocytes that contribute to scar tissue that inhibits regeneration. Herein, we investigated a combinatorial treatment in a chronic cervical hemisection model involving cargo-less nanoparticles (NPs) administered acutely, and a multichannel bridge and microtubule stabilizer delivered chronically. NPs administration acutely for one-week post-injury contributed to improved paw placement on a ladder beam relative to vehicle control. Four weeks after injury, damaged tissue was resected, and a microporous, multichannel PLG bridge was inserted to reduce scar tissue and provide a substrate for axon regrowth. Epothilone D (epoD), a microtubule stabilizer, was also administered to further decrease fibrotic scar formation and improve axon elongation. Mice receiving a scaffold with NP treatment or epoD treatment had improved motor performance, but the combination of NP and epoD maximally improved function. In conjunction with this improved performance, mice that received NPs or epoD exhibited increased neuromuscular junction innervation, robust axon growth into the bridge, and both oligodendrocyte and Schwann-cell myelination of regenerating axons. Collectively, these results suggest that a combinatorial treatment plan targeting inflammation and scarring, a substrate for growth, and growth-promoting factors can improve motor performance following SCI.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00742"},"PeriodicalIF":6.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Black gas, bright future: H₂S based therapeutics for neurodegenerative disorders.","authors":"Jordan L Morris, Jordan J Lee, Russell E Morris, Jan Lj Miljkovic","doi":"10.1016/j.neurot.2025.e00755","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00755","url":null,"abstract":"<p><p>From shaping Earth's earliest anoxic seas to quietly orchestrating cellular life today, hydrogen sulfide (H₂S) has journeyed from ancient toxin to modern therapeutic candidate. Once abundant in Earth's primordial environment, H₂S has reemerged as a critical endogenous gasotransmitter in modern biology. Within the central nervous system, H₂S regulates redox homeostasis, mitochondrial bioenergetics, inflammatory signalling, and neuronal excitability. A key mechanism involves post-translational modification of protein cysteine residues (persulfidation), reactions with metal centres, and scavenging of reactive oxygen and nitrogen species, thereby influencing diverse cellular processes. Dysregulation of H₂S metabolism, whether deficient or excessive, is increasingly implicated in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's disease, Down syndrome, and in stroke and traumatic brain injury. This review focuses on neuronal aspects of H₂S biology and therapeutic relevance in these conditions. Restoration of H₂S signalling in preclinical models improves cognitive and motor function, reduces neuropathology, and preserves mitochondrial integrity. Therapeutic innovation has produced a variety of H₂S donors, including slow-releasing compounds, organelle-targeted agents, and emerging nanomaterial platforms such as polymer-based and metal-organic frameworks for precision CNS delivery. Natural compounds such as ergothioneine, a sulfur-containing antioxidant, are also gaining attention as potential modulators of endogenous H₂S pathways. Future directions include integration of H₂S therapies with genetic targeting tools and elucidation of their interactions with other gasotransmitters and gut-brain axis signalling. Although clinical trials remain limited, the convergence of donor chemistry, molecular biology, and delivery technologies positions H₂S-based therapeutics as a promising frontier for treating neurodegeneration and acute neural injuries.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00755"},"PeriodicalIF":6.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pleiotropic regulatory mechanisms and targeted therapeutic prospects of Galectin-3 in aging-related diseases.","authors":"Jiayu Yuan, Xiaoyu Dong, Yan Gao, Jianfei Nao","doi":"10.1016/j.neurot.2025.e00744","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00744","url":null,"abstract":"<p><p>Aging is a major risk factor for numerous chronic diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), atherosclerosis (AS), type 2 diabetes mellitus (T2DM), osteoarthritis (OA) and age-related macular degeneration (AMD). Galectin-3 (Gal-3), a unique β-galactoside-binding lectin, has emerged as a critical mediator in the pathogenesis of AD and other age-related disorders by modulating key mechanisms such as inflammation, oxidative stress, and apoptosis. While emphasizing neurological disorders (AD, PD), this review also examines Gal-3's role in systemic age-related conditions (T2DM, AS, OA, AMD) that frequently co-occur with or influence neurodegeneration. This review summarizes current knowledge on the expression patterns, molecular mechanisms, and therapeutic potential of Gal-3 in aging-related diseases. Elevated Gal-3 levels have been detected in the brain tissue and cerebrospinal fluid of AD patients, where it contributes to multiple pathological processes, including microglia-driven neuroinflammation, Aβ plaque deposition, tau hyperphosphorylation, oxidative damage, and neuronal apoptosis. Furthermore, Gal-3 upregulation is observed across various age-related diseases and correlates with disease progression, underscoring its potential as a diagnostic biomarker and therapeutic target. Preclinical studies demonstrate that Gal-3-targeted interventions-including small-molecule inhibitors (e.g., TD-139), natural compounds (e.g., modified citrus pectin), and other pharmacological agents-exert neuroprotective, anti-inflammatory, antioxidant, and anti-apoptotic effects by binding to Gal-3 and modulating its activity in animal models, offering promising avenues for multi-disease treatment. However, the dual roles and complex regulatory networks of Gal-3 present challenges for clinical translation, requiring context-specific therapeutic approaches tailored to distinct disease mechanisms. Future research should focus on elucidating tissue-specific mechanisms and optimizing combination therapies to enable precise targeting of aging-related pathologies.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00744"},"PeriodicalIF":6.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective role of DNTαβ Cell transplantation on modulating immune microenvironment in spinal cord injured mice.","authors":"Yingli Jing, Zihan Li, Fan Bai, Yitong Yan, Yan Li, Weijin Liu, Qiuying Wang, Lixi Zhao, Yanbing Zhu, Guangyong Sun, Dong Zhang, Jianjun Li, Yan Yu","doi":"10.1016/j.neurot.2025.e00743","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00743","url":null,"abstract":"<p><p>Traumatic spinal cord injury (SCI) is a common disabling condition characterized by a disrupted immune microenvironment that significantly hinders neural regeneration. In recent years, CD3⁺CD4^-CD8^- double-negative T cells (DNT cells) have garnered considerable attention due to their multifaceted roles in immune regulation. Flow cytometry data indicate a significant increase in the proportion of DNT cells following SCI. Single-cell sequencing further demonstrates the heterogeneity of DNT cells, with CD3⁺TCRαβ⁺CD4^-CD8^-NK1.1^- T cells (DNTαβ) potentially playing an immune regulatory role. Accordingly, we hypothesize that the transplantation of DNTαβ cells could improve the immune microenvironment in the spinal cord. To test this hypothesis, we obtained DNTαβ cells for SCI treatment through flow cytometric sorting. Behavioral assessments indicated that both in situ injection and tail vein injection of DNTαβ cells significantly promoted the recovery of motor function in mice with SCI. Immunohistochemical analysis further revealed that DNTαβ cells can inhibit glial proliferation and promote neuronal survival and myelination. Transcriptomic sequencing data also supported the role of DNTαβ cell transplantation in modulating immune responses through the Gzmb and IFN pathways, to promote early repair and neuroprotection following SCI. Our findings suggest that exogenous supplementation of DNTαβ cells can regulate the immune microenvironment to enhance neural regeneration after SCI, providing new therapeutic strategies and data support for cellular therapies following SCI.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00743"},"PeriodicalIF":6.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurocognitive and neurobiological effects of low dose organophosphate exposure.","authors":"Kelly M C Nguyen, Devyani Swami, Nandini Goyal, Mihika G Jalwadi, Munjal M Acharya, Janet E Baulch","doi":"10.1016/j.neurot.2025.e00733","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00733","url":null,"abstract":"<p><p>Organophosphates (OPs) have been used as nerve agents in the Persian Gulf Wars and terrorist attacks in Japan and the United Kingdom. While high doses of OPs may be lethal, lower dose OP exposures can lead to neurotoxic consequences for the central nervous system (CNS), which manifest as cognitive dysfunction including anxiety, depression, and learning and memory deficits. Therefore, OP toxicity poses a threat for warfighters, first responders, clean-up workers and civilians. Because the CNS effects of low dose OP exposures may be persistent, it is crucial to find countermeasures to mitigate any long-term neurological damage. This study evaluated the effect of a very low dose OP, metrifonate (MFT, 80 ​mg/kg, i.p.) and the efficacy of an orally available, small molecule adenosine kinase (ADK) inhibitor, ABT-702 (1.6 ​mg/kg, i.p., six daily doses), to ameliorate OP-induced long-term neurotoxicity. One-month post-exposure, MFT selectively impaired medial pre-frontal cortex (mPFC)-dependent executive function gauged by the puzzle box task, that was alleviated by ABT-702 treatment. MFT showed subtle effects on motor function at early (48h to one-week) post-exposure intervals without impacting spatial recognition memory or the hippocampal milieu. Dual immunofluorescence staining and volumetric quantification indicated reduced microglial activation and hypertrophic astrocytes post-ABT-702 treatment in MFT-exposed mice. ABT-702 also restored post-synaptic density protein, PSD-95, in the MFT-exposed mPFC. These data indicate that ABT-702 treatment protects mPFC-dependent function post-MFT exposure. The subtle impact of low dose MFT exposure on CNS function should be further evaluated at other time points and doses.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00733"},"PeriodicalIF":6.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rescue of neurologic disease in mucopolysaccharidosis type II mice via AAV-mediated liver delivery of brain-penetrating iduronate-2-sulfatase.","authors":"Xiu Jin, Qin Ye, Xiaoyi Wu, Jing Su, Li Song, Jiamei Fu, Qiuxia Xu, Min Luo, Fanfei Liu, Chengda Ren, Ming Hu, Man Liu, Yifang An, Qiqi Li, Manjun Li, Yang Yang","doi":"10.1016/j.neurot.2025.e00741","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00741","url":null,"abstract":"<p><p>Mucopolysaccharidosis type II (MPS II) is a neurodegenerative lysosomal storage disorder (LSD) caused by inherited mutations in the iduronate-2-sulfatase (IDS) gene. Approximately two-thirds of patients exhibit severe central nervous system (CNS) involvement and cognitive impairment, which remain unaddressed by conventional enzyme replacement therapy (ERT) due to the inability of wild-type IDS to cross the blood-brain barrier (BBB). To overcome this limitation, we engineered a brain-penetrant IDS variant, eBT-IDS4, which retained enzymatic activity and demonstrated enhanced BBB transcytosis in vitro. We then evaluated a liver-directed gene therapy approach using an adeno-associated virus 8 (AAV8) vector encoding eBT-IDS4 under the control of a liver-specific promoter (LSP) in an adult MPS II mouse model. Intravenous administration of AAV8.LSP.IVS2.eBT-IDS4 resulted in sustained supraphysiological IDS activity and normalization of glycosaminoglycan (GAG) levels in peripheral tissues. Notably, this strategy achieved 89 ​% of wild-type IDS activity in the brain, leading to complete correction of neuropathology and reversal of cognitive deficits in 8-month-old MPS II mice. These findings support a promising, minimally invasive gene therapy strategy for treating MPS II and other neurodegenerative LSDs.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00741"},"PeriodicalIF":6.9,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TNFR2 signaling shapes the sex-specific remyelinating properties of microglia after experimental stroke.","authors":"Stefano Raffaele, Francesca Carolina Mannella, Estrid Thougaard, Pernille Vinther Nielsen, Morten Blickfeldt-Eckhardt, Eva Tolosa, Justine Münsterberg, Tim Magnus, Jens D Mikkelsen, Mathias Gelderblom, Helle Hvilsted Nielsen, Bettina Hjelm Clausen, Roberta Brambilla, Marta Fumagalli, Kate Lykke Lambertsen","doi":"10.1016/j.neurot.2025.e00745","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00745","url":null,"abstract":"<p><p>Microglial tumor necrosis factor receptor 2 (TNFR2) has emerged as a critical modulator of neuroinflammation and repair following ischemic stroke. Here, we investigated the sex-specific role of TNFR2 in regulating microglial responses during the acute and subacute phases after stroke. Using a conditional knockout model, we found that TNFR2 ablation in microglia exerted opposite effects on morphology, reactivity, and phagocytic capacity in female compared to male mice at day 5 post-stroke. In females, TNFR2 deletion impaired microglial reactivity and myelin debris clearance, reduced oligodendrocyte maturation, and worsened motor and cognitive recovery. In contrast, TNFR2 ablation in males produced milder and occasionally opposing effects, without affecting functional outcomes. Analysis of cerebrospinal fluid from stroke patients revealed a positive association between TNFR2 and microglial phagocytosis markers (TREM2, Galectin-3), particularly in females, which may be useful to track microglial pro-regenerative state during rehabilitation and therapy. These findings identify TNFR2 as a sex-dependent regulator of microglial function and highlight its potential as a therapeutic target for enhancing post-stroke recovery, especially in women.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00745"},"PeriodicalIF":6.9,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR-edited iPSCs reveal BSN gene mutations induce neuronal hyperexcitability via astrocyte lipid accumulation.","authors":"Haiying Chen, Shanshan Fan, Kanglian Chen, Feilong Wang, Meiting Lu, Yide Wu, Hailian Lu, Jinliang Li","doi":"10.1016/j.neurot.2025.e00740","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00740","url":null,"abstract":"<p><p>Mutations in the BSN gene, encoding the presynaptic protein Bassoon, are implicated in epilepsy, but their impact on astrocytes remains unclear. Using CRISPR/Cas9, we introduced patient-derived BSN mutations (p.M1903V and c.5672insCG) into human induced pluripotent stem cells (iPSCs) and differentiated them into astrocytes. We found that mutant astrocytes exhibited significant lipid accumulation, evidenced by elevated free cholesterol, reduced arginase activity, and increased lipid droplets. Proteomic analysis revealed upregulation of lipid metabolism regulators, such as APOE and FASN. Electrophysiological recordings showed impaired Kir4.1 potassium channel function, depolarized resting membrane potential, and increased capacitance in mutant astrocytes following kainic acid stimulation. Co-culture experiments with neurons demonstrated that BSN-mutant astrocytes led to reduced neurite outgrowth, elevated neuronal apoptosis, increased pro-inflammatory cytokines (IL-1β, TNF-α), and neuronal hyperexcitability. These findings demonstrate that BSN mutations disrupt astrocyte lipid homeostasis and impair neurosupportive functions, thereby driving neuronal hyperexcitability. This study establishes astrocytes as critical mediators of epilepsy pathogenesis in BSN-related disorders and highlights lipid metabolism as a potential therapeutic target.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00740"},"PeriodicalIF":6.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural bridging achieves transcutaneous regulation of vagus nerve function and treatment of depressive disorders.","authors":"Fengchi Sun, Xiangmeng Su, Yiyuan Wang, Zhen Pang, Shuai Zhu, Siwei Xu, Xiaoyun Guo, Wendong Xu, Changrui Chen, Yundong Shen","doi":"10.1016/j.neurot.2025.e00738","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00738","url":null,"abstract":"<p><p>Vagus nerve stimulation (VNS) represents a neuromodulation technique that has shown potential in the treatment of various diseases. However, conventional VNS therapy is constrained by the requirement for implanted electrodes, primarily due to the scarcity of appropriate vagal cutaneous branches. Here, a neural bridging method was employed to connect the sensory nerve with the vagus nerve, thereby facilitating transcutaneous modulation of autonomic nerve function and addressing depressive disorders. Results showed that end-to-side neurorrhaphy induced robust axonal regeneration while preserving vagus nerve integrity. Neural tracing confirmed cervical nerve-to-nucleus tractus solitarius projections. Postoperative auricular stimulation significantly evoked 3.46-fold higher c-Fos+ neurons in the nucleus tractus solitarius versus sham controls. In depressed mice, this approach normalized behavioral deficits. Further investigations revealed concomitant improvements in non-rapid eye movement sleep architecture and suppression of hippocampal neuroinflammatory pathways (e.g., TNF, RNA-seq p ​< ​0.001). Together, this study developed a neural-bridging approach in mice that surgically connected a cutaneous sensory nerve to the cervical vagus nerve. Subsequent gentle auricular stimulation robustly activated the brainstem vagal nucleus and improved depression-like behaviors and sleep, alongside reduced hippocampal inflammatory signaling. As a preclinical proof-of-concept study, translational feasibility and long-term safety in humans require rigorous evaluation.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00738"},"PeriodicalIF":6.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world effectiveness and safety of ofatumumab in relapsing-remitting multiple sclerosis: Insights from naïve and switch patients.","authors":"Clara G Chisari, Salvatore Lo Fermo, Salvatore Iacono, Giuseppe Schirò, Francesca Ruscica, Sabrina Realmuto, Sebastiano Bucello, Paolo Ragonese, Giuseppe Salemi, Francesca Matta, Simona Toscano, Salvatore Cottone, Luigi Maria Edoardo Grimaldi, Francesco Patti","doi":"10.1016/j.neurot.2025.e00724","DOIUrl":"https://doi.org/10.1016/j.neurot.2025.e00724","url":null,"abstract":"<p><p>Ofatumumab (OFA), a fully human anti-CD20 monoclonal antibody, has shown promising efficacy in treating relapsing multiple sclerosis (RMS) by depleting B cells and reducing disease activity. This real-world, prospective, multicenter study evaluated the effectiveness and safety of OFA in treatment-naïve patients and those transitioning from other disease-modifying therapies (DMTs), including natalizumab (NTZ). RRMS patients initiating OFA at seven MS centers in Sicily and treated for at least 12 months were analyzed. Outcomes included annualized relapse rates (ARR), Expanded Disability Status Scale (EDSS), and the percentage of patients free from relapse, MRI activity, and confirmed EDSS worsening (CEW). Of 213 patients, 66 (30.9 ​%) were naïve and 147 (69.1 ​%) were switchers. At 12 months, both groups showed comparable CEW-free (93.9 ​% vs. 93.8 ​%), relapse-free (92.4 ​% vs. 93.2 ​%), and MRI activity-free (84.8 ​% vs. 85.0 ​%) proportions. Within the high-efficacy group, NTZ-switchers showed significantly better MRI outcomes than those switching from other agents, while CEW-free and relapse-free rates remained similar. OFA was well tolerated with no serious adverse events. Predictors of non-response included high baseline MRI activity, disease duration >10 years, and prior NTZ and non-NTZ high-efficacy DMTs. These findings support OFA as a safe and effective option for RRMS across patient subtypes.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00724"},"PeriodicalIF":6.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}