Complement-based Therapeutics in Demyelinating Disease

描述（由申请人提供）：多发性硬化症（MS）是最常见的自身免疫性脱髓鞘疾病，影响全球数百万人。在过去的二十年中，治疗多发性硬化症的治疗选择已经变得可用，但它们在有效性和安全性方面受到限制，并且困扰着其他人（Tysabri，抗VLA-4抗体）。目前可用的治疗方案针对复发缓解型多发性硬化症，对进展型多发性硬化症无效。基于临床病理学和实验性自身免疫性脑脊髓炎（EAE） （ms的动物模型）的研究，补体系统作为先天免疫反应的主要组成部分，有助于脱髓鞘疾病的发生和进展，这一点已经得到了很好的证实。分析死后MS病变的免疫组织化学研究表明，在活动性和慢性活动性MS病变中都有大量补体激活片段的沉积，并在所谓的II型MS中涉及补体。在我们实验室的EAE研究中，我们使用了许多补体突变和转基因小鼠，表明抑制替代补体途径和C3转化酶可显著保护疾病。我们的初步研究表明，抗因子B抗体（一种替代途径的抑制剂）或CR2-Crry（一种重组工程C3转化酶抑制剂）治疗可以显著降低EAE的严重程度。综上所述，这些数据表明，抑制补体可能是多发性硬化症的一种可行的治疗选择，然而，一些重要的问题仍然存在，特别是关于治疗正在进行的疾病。我们假设，通过多种机制抑制补体的早期激活代表了脱髓鞘疾病的一种可行的治疗方法，独立于小鼠品系和诱导疾病的髓鞘抗原。为了解决这一假设，我们提出了以下具体目标：1)确定疾病发展后替代途径（抗因子B抗体）与C3转换酶（CR2-Crry）抑制剂的有效性；2)确定补体抑制是否有效减轻EAE的发展，而不管疾病诱导髓磷脂来源抗原是什么。如果成功，这些研究将为临床前转化工作奠定基础。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is the most common autoimmune demyelinating disease, affecting millions of individuals worldwide. In the last two decades, therapeutic options for the treatment of MS have become available, however they are limited in terms of effectiveness and safety issues have plagued others (Tysabri, anti- VLA-4 antibody). The currently available treatment options target relapsing remitting forms of MS and are not effective in the more progressive forms of the disease. These limitations highlight a significant unmet treatment need for MS. It is well established that the complement system, a major component of the innate immune response, contributes to the development and progression of demyelinating disease, based on clinical pathology and studies using experimental autoimmune encephalomyelitis (EAE), the animal model for MS. Furthermore, immunohistochemical studies analyzing postmortem MS lesions have demonstrated the deposition of numerous complement activation fragments in both active and chronic active MS lesions, and implicated complement in so- called Type II MS. In EAE studies from our laboratory, we have shown, using a number of complement mutant and transgenic mice, that inhibition of the alternative complement pathway and the C3 convertase confers significant protection from disease. Our preliminary studies demonstrate significant attenuation of EAE severity on treatment with anti-factor B antibody (an inhibitor of the alternative pathway or CR2-Crry (a recombinantly engineered C3 convertase inhibitor. Together these data indicate that inhibition of complement may be a viable therapeutic option in MS, however several important questions remain, particularly with respect to treatment of ongoing disease. We hypothesize that inhibition of complement early in activation by multiple mechanisms represents a viable therapeutic approach in demyelinating disease, independent of the mouse strain and disease-inducing myelin antigen. To address this hypothesis, we propose the following specific aims: 1) determine the effectiveness of alternative pathway (anti-factor B antibody) versus C3 convertase (CR2-Crry) inhibitors after disease development and, 2) determine if complement inhibition is effective in attenuating EAE development regardless of the disease inducing myelin-derived antigen. If successful, these studies will set the stage for pre-clinical translational efforts. PUBLIC HEALTH RELEVANCE: The utility of complement therapeutics in demyelinating disease remains poorly explored. Studies in this application are designed to examine the role of C3 convertase and factor B inhibitors in reducing established disease in experimental autoimmune encephalomyelitis, the animal model for multiple sclerosis.