Complement-based Therapeutics in Demyelinating Disease

脱髓鞘疾病中基于补体的治疗

• 批准号: 8117574
• 负责人: Scott R BARNUM
• 金额: $ 18.31万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117574
• 关键词: Address; Affect; Alternative Complement Pathway; Animal Model; Antibodies; Antigens; Attenuated; Autoimmune Process; Autopsy; C57BL/6 Mouse; Chronic; Clinical Pathology; Clinical Research; Complement; Complement 3 Convertase; Complement 3d Receptors; Complement Activation; Complement Factor B; Complement Inactivators; Copaxone; Data; Demyelinating Diseases; Deposition; Development; Disadvantaged; Disease; Effectiveness; Engineering; Experimental Autoimmune Encephalomyelitis; Immune response; Individual; Integrin alpha4beta1; Interferons; 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，影响全球数百万人。在过去的二十年中，治疗MS的治疗选择已经变得可用，但是它们在有效性方面是有限的，并且安全性问题已经困扰着其他人（Tysabri，抗VLA-4抗体）。目前可用的治疗方案针对MS的复发缓解型，并且在疾病的更进展形式中无效。这些局限性突出了MS的显著未满足的治疗需求。基于临床病理学和使用实验性自身免疫性脑脊髓炎（EAE）（MS的动物模型）的研究，已经充分确定补体系统（先天免疫应答的主要组分）有助于脱髓鞘疾病的发展和进展。分析死后MS损伤的免疫组织化学研究已经证明了在活动性和慢性活动性MS损伤中大量补体激活片段的沉积，在我们实验室的EAE研究中，我们已经使用许多补体突变体和转基因小鼠表明，抑制补体旁路途径和C3转化酶可显著保护疾病。我们的初步研究表明，用抗因子B抗体（旁路途径的抑制剂）或CR2-Crry（重组工程化的C3转化酶抑制剂）治疗显著减轻了EAE的严重程度。总之，这些数据表明，抑制补体可能是MS的一种可行的治疗选择，但仍存在几个重要的问题，特别是关于正在进行的疾病的治疗。我们假设，通过多种机制抑制补体激活早期代表了脱髓鞘疾病的可行治疗方法，独立于小鼠品系和疾病诱导髓鞘抗原。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）相对于C3转化酶（CR2-Crry）抑制剂的有效性，以及2）确定补体抑制是否有效减弱EAE发展，而不管疾病诱导髓鞘衍生抗原如何。如果成功，这些研究将为临床前转化工作奠定基础。 公共卫生相关性：补体疗法在脱髓鞘疾病中的应用仍然很少。本申请中的研究旨在检查C3转化酶和因子B抑制剂在减少实验性自身免疫性脑脊髓炎（多发性硬化症的动物模型）中已建立的疾病中的作用。