Novel Anti-Proteinuric Strategies Targeting Podocytes

项目摘要 肾小球功能障碍是蛋白尿肾病的主要原因。占比> 90% 终末期肾病（ESRD）病例，仅在美国治疗费用就超过200亿美元。目前， 蛋白尿性肾病用诸如抗高血压药的药物治疗，所述药物具有全身活性， 暂时缓解症状。足细胞对于肾小球滤过器的形成是必不可少的。 由于足细胞损伤是各种蛋白尿肾病发病机制的早期事件， 如局灶节段性肾小球硬化（FSGS）和糖尿病肾病（DN），这些细胞是一种极好的 靶向治疗的发展目标。然而，为合理发展 足细胞定向治疗由于缺乏任何定量的基于细胞的 筛选试验此外，虽然许多特定的遗传异常和环境因素背后， 足细胞损伤的患者已被确定，翻译这种机制的见解，以药物 发现的努力非常缺乏。最近，我们在解决这些问题方面取得了重大进展， 挑战（在提案中作为初步数据提出），其中包括-a）开发一种新的 足细胞为基础的高通量筛选（HTS）试验，并使用它来确定24个新的命中， 在体外和体内保护足细胞免受损伤; B）证明我们的足细胞测定可以 准确和可重复地测量来自患者来源的血清或携带足细胞的足细胞损伤 患者特异性遗传缺陷，并表明遗传缺陷可以通过新的小 在敲入动物模型中的分子;和c）开发新的人源化小鼠模型， 蛋白尿肾病，其可用于验证新的命中化合物，以更快地翻译成 诊所这些令人兴奋的发现构成了我们目前提案的基础。我们假设我们的小说 基于足细胞的筛选试验可用于发现新的候选药物， 足细胞在病人相关的设置。我们进一步提出了基于药物化学的优化， 已确认的命中。此外，我们假设在这种情况下，人足细胞与患者血清的适应性 分析系统将使我们能够识别独特的足保护化合物。最后，我们还假设， 包括人源化小鼠肾损伤模型将为我们提供改进的HIT体内模型 验证，以便我们能够快速提名候选药物，用于开发人类 患者在未来我们还提出了一个独立的，在体内验证我们的命中。我们的长期目标是 开发靶向和稳定足细胞的新型治疗剂作为治疗 蛋白尿肾病

Project Summary Glomerular dysfunction is a leading cause of the proteinuric kidney disease. It accounts for >90% of end stage renal disease (ESRD) cases, costing >$20B for treatment in the US alone. Currently, proteinuric kidney disease is treated with drugs, such as anti-hypertensives, that are systemically active to temporarily relieve the symptoms. Podocytes are essential for the formation of the glomerular filter. Because podocyte injury is an early event in the pathogenesis of various proteinuric kidney diseases, such as focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy (DN), these cells are an excellent target for the development of targeted therapeutics. However, efforts for the rational development of podocyte-directed therapeutics have been hampered by the absence of any quantitative cell-based screening assay. Moreover, while many specific genetic abnormalities and environmental factors behind podocyte injury in patients have been identified, translation of such mechanistic insights into drug discovery efforts is sorely lacking. Recently, we have made significant progress in addressing these challenges (presented as preliminary data in the proposal), which includes – a) development of a novel podocyte cell-based high throughput screening (HTS) assay and using it to identify 24 novel hits that protect podocytes from damage in vitro and in vivo; b) demonstration that our podocyte assay can accurately and reproducibly measure podocyte injury from patient-derived sera or in podocytes carrying patient-specific genetic defects, and showing that the genetic defects can be rescued via novel small molecules in knock-in animal models; and c) development of a novel humanized mouse model of proteinuric kidney disease, which can be used to validate novel hit compounds for faster translation into clinic. These exciting findings form the basis of our current proposal. We hypothesize that our novel podocyte-based screening assay could be used to discover novel candidate drugs that directly act on podocytes in patient-relevant settings. We further propose medicinal chemistry based optimization of confirmed hits. Furthermore, we hypothesize that adaptation of human podocytes with patient sera in this assay system will allow us to identify unique podo-protective compounds. Finally, we also hypothesize that inclusion of a humanized mouse model of kidney injury will provide us an improved in vivo model for hit validation so that we can rapidly nominate drug candidates for development into therapeutics for human patients in the future. We also propose an independent, in vivo validation of our hits. Our long-term goal is to develop novel therapeutic agents that target and stabilize podocytes as a strategy for the treatment of proteinuric kidney disease.