Establishing VEP as a quantitative biomarker for remyelination using transgenic models for gain and loss of function

使用功能获得和丧失的转基因模型建立 VEP 作为髓鞘再生的定量生物标志物

• 批准号: 10391432
• 负责人: Ari J Green
• 金额: $ 36.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391432
• 关键词: Ablation; Acute; Animal Model; Anterior; Axon; Biological Markers; Brain; Cell Differentiation process; Cells; Central Nervous System Diseases; Chemicals; Chronic; Clinic; Clinical; Cuprizone; Data; Demyelinations; Development; Disease remission; Drug Screening; Electron Microscopy; Electrophysiology (science); Exhibits; Experimental Autoimmune Encephalomyelitis; Exposure to; Failure; Genetic; Genetic Engineering; Histologic; Histology; Human; Human Biology; Immune; Immune response; Immunological Models; Immunomodulators; Inflammation; Inflammatory; Injections; Injury; Knockout Mice; Lesion; Lysophosphatidylcholines; Macaca; Magnetic Resonance Imaging; Maintenance; Measurement; Measures; Mediating; Medicine; Methods; Modeling; Modification; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Neurologic Dysfunctions; Oligodendroglia; Optic Nerve; Outcome; Pattern; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physiological; Positioning Attribute; Pre-Clinical Model; Primates; Protocols documentation; Recovery; Reproducibility; Retina; Rodent; Rodent Model; Role; Signal Transduction; Spinal Cord; Stains; System; Techniques; Testing; Therapeutic; Therapeutic Effect; Transgenic Model; Travel; Treatment Efficacy; Uncertainty; Validation; Visual Pathways; Visual evoked cortical potential; Work; base; chronic demyelination; clinical development; clinical investigation; conditional knockout; disability; immunomodulatory therapies; improved; loss of function; monocular; multiple sclerosis patient; multiple sclerosis treatment; neuron loss; oligodendrocyte precursor; optic nerve disorder; pre-clinical; precursor cell; preservation; programs; remyelinating agent; remyelination; restoration; stem cells; temporal measurement; therapeutic target; therapy development; tool

Multiple sclerosis (MS) is an immune mediated disease of the central nervous system in which an aberrant immunological response targets myelin, leading to short-term neurological dysfunction (exacerbations) and ultimately to permanent disability. Demyelination of axons is potentially a major contributor to irreversible neuronal loss and secondary irrecoverable disability. Oligodendrocyte precursor cells (OPCs) are an endogenous pool of oligopotent stem cells capable of replenishing damaged or lost oligodendrocytes and are found throughout the brain and within lesions of MS patients. However, incompletely understood factors appear to inhibit oligodendrocyte differentiation and resultant remyelination after inflammatory injury in MS. The use of EAE as a clinical and immunological model to illuminate MS has contributed significantly to the growing arsenal of immunomodulatory therapies available for treatment. MRI has also been a useful early phase clinical outcome that has helped improve efficiency of selection of compounds for phase III development as immunomodulatory agents. No similar models or methods exist for demonstrating and confirming therapeutic potential for remyelinating agents. In this project we will conclusively establish the histological and ultrastructural correlates of visual evoked potential latency in multiple models of visual pathway demyelination. These systems will allow us to disentangle the role of demyelination from inflammation and axonal loss by using a) genetically engineered models with enhanced and abrogated myelinating capacity, b) a validated remyelinating compound previously assessed by multiple groups in both rodent and human cells as well as rodent spinal cord, c) non-inflammatory demyelinating models using chemical demyelination methods and d) a unique primate monocular chemical demyelinating model. Furthermore, we have completed a phase II clinical trial that clemastine improves latency on visual evoked potentials in human MS patients with chronic optic neuropathy. Our preliminary work suggests that VEP may be more sensitive than clinical scoring for detecting demyelination and/or that the visual pathway itself is sensitive to early injury in EAE. We have optimized a VEP protocol for mice with exceptional reproducibility and high throughput capacity. We have also developed and/or begun working with models capable of dissecting the impact of demyelination, remyelination, inflammation and axonal loss for better understanding the factors that influence VEP signal. This work will help to establish VEP in EAE and confirm the cellular basis of changes on the VEP signal in general. It will thereby resolve a currently unmet need and accelerate the preclinical and early clinical development of therapies for remyelination in MS.

多发性硬化症（MS）是中枢神经系统的免疫介导的疾病，其中异常的 免疫反应靶向髓鞘，导致短期神经功能障碍（恶化）， 最终导致永久性残疾。轴突的脱髓鞘可能是导致不可逆的 神经元丧失和继发性不可恢复的残疾。少突胶质细胞前体细胞（OPCs）是一种 内源性寡能干细胞池能够补充受损或丢失的少突胶质细胞， 在多发性硬化症患者的整个大脑和病变内发现。然而，不完全了解的因素 似乎抑制MS中炎性损伤后少突胶质细胞的分化和由此产生的髓鞘再生。 使用EAE作为阐明MS的临床和免疫学模型， 免疫调节疗法的军火库可用于治疗。MRI也是一个有用的早期阶段 临床结果有助于提高III期开发化合物的选择效率， 免疫调节剂。目前还没有类似的模型或方法来证明和确认治疗 髓鞘再生剂的潜力。 在这个项目中，我们将最终建立视觉诱发的组织学和超微结构的相关性， 多种视觉通路脱髓鞘模型的潜在潜伏期。这些系统将允许我们 通过使用a）基因工程， 具有增强和消除的髓鞘形成能力的模型，B）先前验证的髓鞘形成化合物 在啮齿动物和人细胞以及啮齿动物脊髓中通过多组评估，c）非炎性 使用化学脱髓鞘方法的脱髓鞘模型和d）独特的灵长类单眼化学物质 脱髓鞘模型。此外，我们已经完成了氯马斯汀改善潜伏期的II期临床试验， 对MS慢性视神经病变患者视觉诱发电位的影响。我们的前期工作 提示VEP可能比临床评分更敏感，用于检测脱髓鞘和/或 视觉通路本身对EAE的早期损伤敏感。我们优化了小鼠的VEP方案， 卓越的再现性和高通量能力。我们还开发和/或开始与 模型能够解剖脱髓鞘，髓鞘再生，炎症和轴突损失的影响， 更好地了解影响VEP信号的因素。这项工作将有助于建立EAE的VEP， 一般确认VEP信号变化的细胞基础。这将解决目前尚未解决的 需要并加速MS髓鞘再生疗法的临床前和早期临床开发。

项目成果

Failed remyelination of the nonhuman primate optic nerve leads to axon degeneration, retinal damages, and visual dysfunction.

• DOI: 10.1073/pnas.2115973119
• 发表时间: 2022-03-08
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Sarrazin N;Chavret-Reculon E;Bachelin C;Felfli M;Arab R;Gilardeau S;Brazhnikova E;Dubus E;Yaha-Cherif L;Lorenceau J;Picaud S;Rosolen S;Moissonnier P;Pouget P;Baron-Van Evercooren A
• 通讯作者: Baron-Van Evercooren A

Distinctive waves of innate immune response in the retina in experimental autoimmune encephalomyelitis.

• DOI: 10.1172/jci.insight.149228
• 发表时间: 2021-06-08
• 期刊: JCI insight
• 影响因子: 8
• 作者: Cruz-Herranz A;Oertel FC;Kim K;Cantó E;Timmons G;Sin JH;Devereux M;Baker N;Michel B;Schubert RD;Rani L;Cordano C;Baranzini SE;Green AJ
• 通讯作者: Green AJ