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

多发性硬化症(MS)是一种免疫介导的中枢神经系统疾病，在这种疾病中 免疫反应以髓鞘为靶点，导致短期神经功能障碍(恶化)和 最终导致永久性残疾。轴突脱髓鞘可能是不可逆转的主要原因 神经元丢失和继发性无法恢复的残疾。少突胶质前体细胞是一种 内源性少突胶质干细胞池，能够补充受损或丢失的少突胶质细胞，并 在多发性硬化症患者的大脑和病变内均可发现。然而，不完全了解的因素 抑制MS炎性损伤后的少突胶质细胞分化和由此产生的重新髓鞘形成。 使用EAE作为临床和免疫学模型来阐明多发性硬化症对多发性硬化症的增长做出了重要贡献 阿森纳的免疫调节疗法可供治疗。核磁共振也是一个有用的早期阶段。 有助于提高选择化合物进行III期开发的效率的临床结果为 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 潜在的再生髓鞘制剂。 在这个项目中，我们将最终确定视觉诱发的组织学和超微结构的相关性。 多种视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)基因工程将脱髓鞘的作用从炎症和轴突丢失中分离出来 具有增强和取消的髓鞘能力的模型，b)先前验证的重新髓鞘化合物 由多个小组在啮齿动物和人类细胞以及啮齿动物脊髓中进行评估，c)非炎症性 使用化学脱髓鞘方法的脱髓鞘模型和d)一种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。 多发性硬化症慢性视神经病变患者的视觉诱发电位研究我们的前期工作 提示VEP在检测脱髓鞘方面可能比临床评分更敏感 视觉通路本身对EAE的早期损伤很敏感。我们已经为小鼠优化了VEP方案 出众的重复性和高吞吐能力。我们还开发和/或开始使用 能够解剖脱髓鞘、重新髓鞘形成、炎症和轴突丢失对 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和 从总体上确认VEP信号变化的细胞基础。因此，它将解决目前未满足的问题 需要并加速临床前和早期临床治疗多发性硬化症的方法。

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.