Nephrotic Syndrome Rare Disease Clinical Research Network III

摘要 局灶性和节段性肾小球硬化（FSGS）、微小病变疾病（MCD）和膜性 肾病（MN），表现为肾病综合征（NS），是一种罕见的疾病， 并发症和终末期肾病，产生巨大的个人，社会和经济负担。 NS的临床、基于组织病理学的分类是不充分的，并且未能捕获NS的分子基础。 这些疾病并不能充分预测其自然史或对治疗的反应。精密 医学（PM）方法是必要的，以定义NS在分子方面，以确定治疗靶点， 将患者与治疗相匹配。NEPTUNE应用了一种创新的研究策略，以改善 NS的诊断、管理和治疗。在前两个项目期间， 研究基础设施已经建立，参与者登记，生物样本收集，关键合作 制定并部署了外联战略。NEPTUNE建立了一个强有力的调查基础设施 包括26个学术中心和两个病人兴趣小组，已经招募了750多名严格 表型分析NS参与者的详细临床、组织学、遗传、转录组和蛋白质组数据集。 这一综合信息已纳入海王星知识网， NS研究社区。在患者利益集团NephCure Kidney的大力支持下， 在国际上，NEPTUNE已经建立了强大的培训和辅助研究计划， 从方法开发到成功的II期临床试验。这些重要的进展 导致了对NS临床试验的极大兴趣，目前有超过15项试验处于高级计划或 注册阶段。 在这个更新应用程序中，我们建议利用海王星资源来促进发现，培训， 和外展，因为我们努力改善健康结果的个人受NS。总体目标是 将PM方法应用于NS，利用在 过去9年。NEPTUNE将实施这一PM战略，以允许发现新的治疗靶点， 部署在当前资助周期中开发的患者分层方法，以帮助确定合适的试验， 在正确的时间选择正确的患者：患者分层方法将用于有针对性的入组， 临床试验患者将在疾病出现时或随访肾功能时接受强化分析。 活组织检查，以便将疾病机制与正在进行的临床试验相匹配， 与该领域的领先公司建立私人伙伴关系。培训、试点和辅助研究项目将 继续获得NKI的大量资金支持。NEPTUNE将继续与Lay保持接触 社区，临床医生，科学家，监管机构和制药行业，以确定和移动 通过有效的NS转化研究管道，为我们的患者提供治疗目标。

ABSTRACT Focal and Segmental Glomerulosclerosis (FSGS), Minimal Change Disease (MCD) and Membranous Nephropathy (MN), presenting as Nephrotic Syndrome (NS), are rare diseases causing catastrophic complications and end stage kidney disease, generating enormous individual, societal and economic burdens. The clinical, histopathology-based taxonomy of NS is inadequate and fails to capture the molecular bases of these diseases and does not adequately predict their natural history or response to therapy. A Precision Medicine (PM) approach is necessary to define NS in molecular terms, to identify therapeutic targets and match patients to treatments. NEPTUNE was applied an innovative, investigational strategy to improve the diagnosis, management and treatment of NS. In the first two project periods, a translational and clinical research infrastructure has been established, participants enrolled, biosamples collected, key collaborations forged and an outreach strategy deployed. NEPTUNE has established a robust investigative infrastructure encompassing 26 academic centers and two patient interest groups, has recruited more than 750 rigorously phenotyped NS participants with detailed clinical, histological, genetic, transcriptomic and proteomic data sets. This comprehensive information has been integrated in the NEPTUNE Knowledge Network for easy access by the NS research community. With substantial support from the patient interest group NephCure Kidney International, NEPTUNE has established robust training and ancillary study programs with 112 ancillary studies ranging from methods development to successful Phase II clinical trials. These critical advances have resulted in a significant interest in NS clinical trials, with more than 15 trials now in the advanced planning or enrollment phase. In this renewal application, we propose to leverage the NEPTUNE resources to catalyze discovery, training and outreach as we strive to improve health outcomes for individuals affected by NS. The overarching goal is to apply a PM approach to NS, leveraging the extensive NEPTUNE Knowledge Network established over the past 9 years. NEPTUNE will implement this PM strategy to permit discovery of novel therapeutic targets and deploy the patient stratification approach developed in the current funding cycle to help identify the right trial for the right patient at the right time: Patient stratification approaches will be utilized for targeted enrollment into clinical trials. Patients will undergo intense profiling at the time of disease presentation or at follow-up renal biopsy in order to match the disease mechanism active with ongoing clinical trials in a precompetitive, public private partnership with leading companies in the field. Training, pilot and ancillary study programs will continue with significant funding support from NKI. NEPTUNE will maintain its engagement with lay communities, clinicians, scientists, regulatory agencies and the pharmaceutical industry to identify and move therapeutic targets to our patients through an effective translational research pipeline for NS.