Targeted Therapies for Myasthenia Gravis

描述（由申请人提供）：重症肌无力（MG）是一种抗体介导的自身免疫性疾病，其损害神经肌肉接头功能。 该疾病可能涉及骨骼肌弥漫性产生危及生命的虚弱，但也产生眼肌功能障碍，导致严重的视力残疾。 重症肌无力的最终效应机制是在神经肌肉接头处形成补体的膜攻击复合物。 补体调节蛋白通常作为补体激活的负调节物起重要作用。 我们的初步研究和已建立的疾病机制强烈支持加强补体形成的负调节作为肌无力治疗的策略。 本研究将补体、眼外肌生物学和生理学、重症肌无力病理生理学和药物开发领域的现有研究者的优势编织在一起，以产生针对重症肌无力神经肌肉接头病理学的补体抑制剂疗法。 研究人员建议通过首先在三个水平上评估补体介导的发病机制来实现这一治疗目标：（a）使用DNA微阵列的全基因组谱分析对操作事件和机制进行全局分析，（B）补体调节转录物和蛋白质的特异性测量，和（c）实验性自身免疫性重症肌无力动物模型中骨骼肌和眼肌性能的结构/功能测量（EAMG）和人MG。 使用转基因动物模型确定补体级联的最有效阶段用于药物开发。 我们的研究小组已经开发出补体抑制剂，并将开发其他针对神经肌肉接头的药物。 这些药物的疗效和耐受性将在未来的临床试验中进行测试。 该疗法的目标是提供一种药物，其将缓和急性肌无力恶化的严重程度，并长期用作辅助剂以限制使用具有不良副作用特征的免疫抑制剂。 由于眼肌对眼肌无力的低度自身免疫过程敏感， 开发的基于抑制剂的治疗应该对治疗视觉功能障碍特别有效。

DESCRIPTION (provided by applicant): Myasthenia gravis (MG) is an antibody-mediated autoimmune disorder, which compromises neuromuscular junction function. The disease may involve skeletal muscle diffusely producing life-threatening weakness, but also produce ocular muscle dysfunction leading to significant visual disability. The final effector mechanism of the myasthenia gravis is the formation of the membrane attack complex of complement at the neuromuscular junction. Complement regulatory proteins normally serve an important role as negative regulators of complement activation. Our preliminary studies and the established disease mechanism strongly support the strategy of enhancing the negative regulation of complement formation as a therapy for myasthenia. This study weaves together the strengths of established investigators in the fields of complement, extraocular muscle biology and physiology, myasthenia gravis pathophysiology, and drug development in order to produce complement inhibitor therapies to target the neuromuscular junction pathology of myasthenia gravis. The investigators propose to achieve this therapeutic goal by first evaluating the complement-mediate pathogenesis at three levels: (a) a global analysis of operative events and mechanisms using genome-wide profiling with DNA microarray, (b) specific measures of complement regulatory transcripts and proteins, and (c) structural/functional measures of skeletal muscle and ocular muscle performance in animal models of experimental autoimmune myasthenia gravis (EAMG) and human MG. The most effective stage of the complement cascade is determined for drug development using transgenic animal models. Our group already has developed complement inhibitors, and additional agents to target the neuromuscular junction will be developed. These will be tested for efficacy and tolerability for use in future clinical trials. The goal of the therapy is to provide a drug, which will moderate the severity of acute myasthenic deteriorations and chronically serve as an adjuvant to limit use of immunosuppressants with poor side effect profiles. Because of the ocular muscles' sensitivity to the low-grade autoimmune process of ocular myasthenia, the complement Inhibitor-based therapy developed should be particularly effective for treatment of visual dysfunction.