Rare Disease Network for Myasthenia Gravis

这项提议的目标是开发一个专门用于重症肌无力(MGNet)的RDCRC。 重症肌无力具有明确的自身抗体介导的损伤的病理生理学。 神经肌肉连接，但存在不同的亚型，具有独特的潜在病理生理学和 病人的需求。治疗方法是存在的，但病人的护理因缺乏治愈而受到影响，很差 治疗的不良反应情况，对现有治疗的高度可变反应，以及较差的 患者报告的生活质量。此外，该领域的治疗开发是 由于所有MG亚型缺乏足够的自然历史数据和缺乏 治疗反应生物标志物。尽管进行了几次严格的临床试验，但失败了 几项2期和3期研究，以支持具有有效生物靶点的药物的疗效 表明MG试验需要改进设计和结果衡量标准。这些 临床上和生物学上不同的亚型的存在使挑战变得更加困难 类型。这些人群是1)早发性乙酰胆碱受体(AChR)抗体(Ab)阳性 MG，主要影响女性；2)晚发性AChR抗体阳性MG，有疾病倾向 男性3)副肿瘤性胸腺瘤相关MG，4)肌肉特异性激酶(穆斯克)抗体 AChR/麝香抗体阴性MG。MGNet提出了以下具体建议 目标：1)通过对患者进行严格的前瞻性监测来增强临床试验准备情况 定义疾病变异性并改进临床结果衡量标准。2)确定治疗方案--预测性 和反应灵敏的生物标记物，以增强早期临床试验的性能和识别 关键试验的合适候选者，改进日常临床实践中的监测，以及 提供潜在的治疗靶点。3)加强年轻调查人员队伍，专注于 关于罕见疾病的职业生涯，特别是MG。4)提高科学家的意识， 医生，并公开关于重症肌无力患者的独特需求。成功 实现我们的目标将建立一个针对疾病的生物样本基础设施 和最佳实践，这将为学术界和产业界提供独特的资源 用于发现和开发临床试验的生物样本。在此期间 我们将培训临床医生科学家，并让患者和科学界参与 临床研究和治疗开发。

The goal of this proposal is to develop a RDCRC dedicated to myasthenia gravis (MGNet). Myasthenia gravis has a well-defined pathophysiology of autoantibody-mediated injury to the neuromuscular junction, but distinct sub-types exist with unique underlying pathophysiology and patient needs. Therapies exist but patient care is compromised by an absence of a cure, poor adverse effect profiles of treatments, highly variable response to existing treatments, and a poor quality of life as reported by patients. Further, therapeutic development in the field is compromised by a lack of adequate natural history data for all MG subtypes and a lack of treatment responsive biomarkers. Despite a few rigorously performed clinical trials, the failure of several phase 2 and 3 studies to support efficacy of drugs with validated biological targets indicates that MG trials require improvements in design and outcome measures. These challenges are made more difficulty by the existence of clinically and biologically distinct sub- types. These groups are 1) early-onset acetylcholine receptor (AChR) antibody (Ab) positive MG, which primarily affects women, 2) late-onset AChR Ab positive MG with a disease bias towards men 3) paraneoplastic thymoma-associated MG, 4) muscle specific kinase (MuSK) Ab positive, and 5) AChR/MuSK antibody negative MG. MGNet proposes the following Specific Aims: 1) Enhance clinical trial readiness through rigorous prospective monitoring of patients to define disease variability and refine clinical outcome measures. 2) Identify treatment-predictive and -responsive biomarkers to enhance early-phase clinical trial performance and identify suitable candidates for pivotal trials, improve monitoring in day-to-day clinical practice, and provide potential therapeutic targets. 3) Enhance the pool of young investigators focusing their careers on rare diseases and specifically MG. 4) Improve the awareness of scientists, physicians, and lay public regarding the unique needs of patients with MG. Successful achievement our objectives will establish a disease-specific infrastructure of biological samples and best practices which will provide a unique resource for academics and industry for access to biological samples for discovery purposes and development of clinical trials. During this process we will train clinician scientists and engage the patient and scientific communities in clinical research and therapeutic development.