Complement-based Therapeutics in Demyelinating Disease

脱髓鞘疾病中基于补体的治疗

• 批准号: 7990776
• 负责人: Scott R BARNUM
• 金额: $ 21.98万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990776
• 关键词: Address; Affect; Alternative Complement Pathway; Animal Model; Antibodies; Antigens; Attenuated; Autoimmune Process; Autopsy; C57BL/6 Mouse; Chronic; Clinical Pathology; Complement; Complement 3 Convertase; Complement Activation; Complement Factor B; Complement Inactivators; Copaxone; Data; Demyelinating Diseases; Deposition; Development; Disadvantaged; Disease; Effectiveness; Encephalomyelitis; Engineering; Experimental Autoimmune Encephalomyelitis; Immune response; Individual; Integrin alpha4beta1; Laboratories; Mouse Strains; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Pathway interactions; Patients; Peptides; Plague; Population; Relapse; Role; Safety; Severities; Severity of illness; Staging; Therapeutic; Transgenic Mice; Tysabri; alternative pathway complement C3 convertase; antibody inhibitor; attenuation; base; complement system; design; inhibitor/antagonist; mutant; pre-clinical; public health relevance; therapeutic effectiveness

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.

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，影响着全世界数百万人。在过去的二十年中，治疗多发性硬化症的治疗方案已经出现，但它们的有效性有限，而且安全问题也困扰着其他人（Tysabri，抗 VLA-4 抗体）。目前可用的治疗方案针对的是复发缓解型多发性硬化症，但对于进展型多发性硬化症无效。这些局限性凸显了多发性硬化症的治疗需求尚未得到满足。根据临床病理学和使用实验性自身免疫性脑脊髓炎 (EAE)（多发性硬化症动物模型）的研究，众所周知，补体系统是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。此外，分析死后多发性硬化症病变的免疫组织化学研究表明，在活动性和慢性活动性多发性硬化症病变中都有大量补体激活片段的沉积，并且与所谓的 II 型多发性硬化症有关。在我们实验室的 EAE 研究中，我们使用大量补体突变体和转基因小鼠证明，抑制补体旁路途径和 C3 转化酶可显着预防疾病。我们的初步研究表明，使用抗因子 B 抗体（旁路途径抑制剂或 CR2-Crry（一种重组工程 C3 转化酶抑制剂）治疗后，EAE 严重程度显着减轻。这些数据共同表明，补体抑制可能是多发性硬化症的可行治疗选择，但仍然存在几个重要问题，特别是关于持续性疾病的治疗。我们假设补体抑制在早期 多种机制的激活代表了脱髓鞘疾病的一种可行的治疗方法，与小鼠品系和诱发疾病的髓磷脂抗原无关。为了解决这一假设，我们提出以下具体目标：1) 确定疾病发展后替代途径（抗因子 B 抗体）与 C3 转化酶 (CR2-Crry) 抑制剂的有效性，2) 确定补体抑制是否有效 无论诱导髓磷脂衍生抗原的疾病如何，均能减弱 EAE 的发展。如果成功，这些研究将为临床前转化工作奠定基础。 公众健康相关性：补体疗法在脱髓鞘疾病中的效用仍未得到充分探索。本申请中的研究旨在检验 C3 转化酶和 B 因子抑制剂在减少实验性自身免疫性脑脊髓炎（多发性硬化症动物模型）中已确定疾病中的作用。