Myelin oligodendrocyte glycoprotein antibody disease: incidence, prevalence, outcome prediction and immunopathology

髓磷脂少突胶质细胞糖蛋白抗体病：发病率、患病率、结果预测和免疫病理学

• 批准号: 10064015
• 负责人: Eoin P Flanagan
• 金额: $ 34.79万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064015
• 关键词: Acute Disseminated Encephalomyelitis; Antibodies; Biological Assay; Biological Markers; Blindness; Case Study; Cells; Cerebrospinal Fluid; Characteristics; Child; Clinic; Clinical; Clinical Laboratory Improvement Amendments; Clinical Trials Design; Coma; Complement; Complement Inactivators; Conflict (Psychology); Data; Decision Making; Demyelinating Diseases; Demyelinations; Dependence; Deposition; Detection; Development; Diagnosis; Diagnostic; Disease; Epidemiology; Evolution; Flow Cytometry; Frequencies; Goals; Healthcare; Immunoglobulin G; Incidence; Inflammatory; Inflammatory Infiltrate; Knowledge; Lead; Lesion; Magnetic Resonance Imaging; Measurement; Measures; Mission; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelitis; Nature; Neuromyelitis Optica; Optic Neuritis; Outcome; Paralysed; Pathogenesis; Pathologic; Pathology; Patient Care; Patients; Pattern; Phase II/III Trial; Physicians; Population; Prevalence; Process; Prognosis; Rare Lesion; Research; Research Proposals; Resource Allocation; Retrospective Studies; Risk Factors; Safety; Serum; Testing; Therapeutic; United States National Institutes of Health; Variant; Wheelchairs; aquaporin 4; base; biobank; blind; clinical practice; clinical trial readiness; cohort; evaluation/testing; experience; immunopathology; improved outcome; injury and repair; innovation; insight; novel; novel therapeutics; oligodendrocyte-myelin glycoprotein; outcome prediction; population based; prognostic value; prospective; public health relevance; recruit; relapse prediction; relapse risk; resource guides; seropositive; standard of care; tissue injury; treatment strategy

PROJECT SUMMARY/ABSTRACT Attacks of myelin oligodendrocyte glycoprotein antibody disease (MOGAD) can render a patient blind, paralyzed or comatose and distinguishing it from other demyelinating diseases such as multiple sclerosis (MS) and aquaporin-4(AQP4)-IgG positive neuromyelitis optica spectrum disorder (NMOSD) is crucial given the major differences in clinical course, treatment and prognosis. Major knowledge gaps in MOGAD are hindering patient care and a barrier to understanding its pathogenesis. The absence of MOGAD incidence and prevalence data and limited knowledge on its epidemiology worldwide directly impacts decisions on when to order MOG-IgG, healthcare planning, clinical trial design and identification of risk factors. The lack of prospective USA data regarding the prognostic value of MOG-IgG titer and persistence impacts treatment decisions. MOG-IgG in cerebrospinal fluid (CSF) is used by clinicians to diagnose MOGAD, yet data on its diagnostic utility is limited compared to the established utility of serum MOG-IgG. The limited data on MRI evolution and immuno-pathology hinders our understanding of MOGAD pathogenesis. The long-term goal is to better diagnose, treat, and understand MOGAD. The objective of this proposal is to determine the incidence and prevalence of MOGAD, the prognostic value of MOG-IgG testing, the diagnostic utility of CSF MOG-IgG, the evolution of MRI lesions and the immunopathology. The central hypotheses (supported by the applicants preliminary data) is that MOGAD epidemiology is similar to AQP4-IgG in the USA but varies by region, that serum MOG-IgG persistence and high titer predict relapse, that CSF MOG-IgG lacks diagnostic utility, that MOGAD MRI lesions resolve more often than MS and that immuno-pathological characteristics of MOGAD can be defined. The rationale is that these findings will directly impact patient care, facilitate clinical trial readiness, enhance understanding of pathogenesis, and lead to development of novel treatments. The hypothesis will be tested by pursuing three specific aims: 1) To determine the population-based incidence, prevalence and frequency of MOGAD versus AQP4-IgG and MS across multiple world regions; 2) To identify the prognostic value of MOG-IgG titer and persistence, assess the utility of CSF MOG-IgG and compare MRI evolution to MS and AQP4-IgG NMOSD; 3) To define the immuno-pathology of MOGAD and compare it to MS and AQP4-IgG NMOSD. To do this we will utilize the largest clinical, sero-epidemiologic and pathologic biobank of demyelinating disease in the world. The approach is innovative because it uses a novel live-cell flow cytometry based MOG-IgG assay developed by the team of applicants. The proposed research is significant because it is expected to guide resource allocation, directly impact patient care by providing guidance on diagnostics and therapeutics and give insight into pathogenesis. Ultimately, the knowledge of immunopathology may lead to the development of novel treatments similar to how complement deposition in AQP4-IgG NMOSD pathology led to phase 2 and 3 trials showing efficacy and safety of eculizumab (a complement inhibitor).

项目摘要/摘要 髓鞘少突胶质细胞糖蛋白抗体病(MOGAD)的发作可使患者失明， 瘫痪或昏迷，并与其他脱髓鞘疾病，如多发性硬化症(MS)区分开来 水通道蛋白-4(AQP4)-IgG阳性的视神经脊髓炎谱系障碍(NMOSD)是至关重要的，因为 在临床病程、治疗和预后方面存在较大差异。MOGAD的主要知识差距正在阻碍 患者护理和了解其发病机制的障碍。没有MOGAD的发病率和 全球范围内的流行数据和对其流行病学的有限知识直接影响着何时 订购MOG-免疫球蛋白、医疗保健计划、临床试验设计和风险因素识别。缺乏 关于MOG-Ig G滴度和持续性影响治疗预后价值的前瞻性美国数据 决定。脑脊液中的MOG-Ig G被临床医生用来诊断MOGAD，但有关其的数据 与已建立的血清MOG-Ig G的诊断效用相比，诊断效用有限。关于磁共振成像的有限数据 进化和免疫病理阻碍了我们对MOGAD发病机制的理解。长期目标是 更好地诊断、治疗和了解MOGAD。这项建议的目标是确定发病率 和MOGAD的患病率，MOG-IgG检测的预后价值，脑脊液MOG-IgG的诊断价值， MRI病变的演变与免疫病理。中心假设(由申请者支持 初步数据)是MOGAD的流行病学与美国的AQP4-IgG相似，但因地区而异，即 血清MOG-Ig G持久性和高滴度预测复发，脑脊液MOG-Ig G缺乏诊断价值 MOGAD MRI病变比MS更容易消失，且MOGAD的免疫病理特征可以 被定义。理由是这些发现将直接影响患者护理，促进临床试验准备， 提高对发病机制的认识，并导致新的治疗方法的发展。假设将是 通过追求三个具体目标进行测试：1)确定基于人群的发病率、流行率和 MOGAD与AQP4-Ig G和MS在世界多个地区的频率；2)确定预后 MOG-Ig G滴度和持久性的价值，评估脑脊液MOG-Ig G的应用价值，并比较MRI与MS的演变 和AQP4-Ig G NMOSD；3)明确MOGAD的免疫病理，并与MS和AQP4-Ig G比较 NMOSD。为此，我们将利用最大的临床、血清流行病学和病理生物库 世界上最严重的脱髓鞘疾病。这种方法是创新的，因为它使用了一种新的活细胞流式细胞术 由申请者团队开发的基于MOG-IgG的检测方法。这项拟议的研究具有重要意义，因为它 预计将指导资源分配，通过提供诊断和指导直接影响患者护理 治疗学和对发病机制的洞察。最终，免疫病理学的知识可能会导致 类似于AQP4-Ig G NMOSD病理中补体沉积的新疗法的发展 导致2期和3期试验显示eculizumab(一种补体抑制剂)的有效性和安全性。