Targeted Therapies for Myasthenia Gravis

描述(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，损害神经肌肉连接功能。这种疾病可能涉及骨骼肌，弥漫性地产生危及生命的虚弱，但也会产生眼肌功能障碍，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连接处形成补体膜攻击复合体。补体调节蛋白通常作为补体激活的负性调节蛋白发挥重要作用。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控作为治疗肌无力的策略。这项研究汇集了补体、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人员的力量，以生产针对重症肌无力神经肌肉接头病理的补体抑制剂疗法。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微阵列的全基因组图谱对手术事件和机制进行全球分析，(B)补体调节转录本和蛋白质的特定测量，以及(C)实验性自身免疫性重症肌无力(EAMG)和人类MG动物模型中骨骼肌和眼肌性能的结构/功能测量。对于药物开发，补体级联的最有效阶段是通过转基因动物模型确定的。我们小组已经开发了补体抑制剂，并将开发更多针对神经肌肉连接的药物。这些药物将在未来的临床试验中进行有效性和耐受性测试。该疗法的目标是提供一种药物，它将缓解急性肌无力恶化的严重程度，并长期作为一种佐剂，限制副作用较差的免疫抑制剂的使用。由于眼肌对眼肌无力的低级别自身免疫过程敏感，补体 开发的基于抑制剂的疗法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.