Rare Disease Network for Myasthenia Gravis

该提案的目标是开发一个专用于重症肌无力（MGNet）的RDCRC。 重症肌无力有一个明确的病理生理学的自身抗体介导的损伤， 神经肌肉接头，但不同的亚型存在独特的潜在病理生理学， 病人的需要。治疗方法存在，但由于缺乏治愈方法，患者护理受到影响， 治疗的不良反应特征，对现有治疗的反应高度可变， 患者报告的生活质量。此外，本领域的治疗发展是 由于缺乏所有MG亚型的足够自然史数据， 治疗反应性生物标志物。尽管进行了一些严格的临床试验， 几项2期和3期研究，以支持具有经验证的生物靶点的药物的疗效 表明MG试验需要改进设计和结局指标。这些 由于存在临床和生物学上不同的亚细胞， 类型这些组是：1）早发性乙酰胆碱受体（AChR）抗体（Ab）阳性 MG，主要影响女性，2）晚发型AChR Ab阳性MG，存在疾病偏倚 3）副肿瘤性胸腺瘤相关MG，4）肌肉特异性激酶（MuSK）Ab AChR/MuSK抗体阴性MG。MGNet提出以下具体建议 目的：1）通过对患者进行严格的前瞻性监测， 定义疾病的变异性并完善临床结果的测量。2)确定治疗预测性 和响应性生物标志物，以增强早期临床试验性能， 关键试验的合适候选人，改善日常临床实践中的监测，以及 提供潜在的治疗靶点。3)加强青年调查员队伍， 罕见疾病，特别是MG的职业生涯。4)提高科学家的认识， 医生和公众对MG患者的独特需求。成功 我们的目标是建立一个针对特定疾病的生物样本基础设施， 和最佳实践，这将为学术界和工业界提供一个独特的资源， 用于发现目的和临床试验的开发的生物样品。在此 在这个过程中，我们将培训临床科学家，并让患者和科学界参与进来， 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.