JAK-STAT Inhibition to Reduce Racial Disparities in Kidney Disease

项目摘要/摘要 肾脏健康方面的差异是美国长期存在的一个重要问题。非洲裔美国人(AA) 占美国人口的13%，罹患终末期肾病的比率是欧洲人的3.5倍 解释了为什么31%的终末期肾病(ESKD)患者是AAA。两种蛋白质编码 载脂蛋白L1(APOL1)基因突变是导致70%的ESKD额外风险的原因 美国医学会。尽管迫切需要治疗载脂蛋白1相关的肾脏疾病(AAKD)，但目前还没有 任何专门针对AAKD的治疗试验。这种需要因代表率严重偏低而变得更加复杂 临床试验中的AAs。在这些需求得到满足之前，美国在肾脏健康方面的差距将持续存在。我们的长- 学期目标是为两种最常见的AAKD形式开发有针对性的治疗方法：APOL1相关病灶 节段性肾小球硬化(FSGS)与高血压慢性肾脏病(HTN-CKD) 以减轻美国汽车协会之间不同的ESKD负担。该特定应用程序的目标是以 APOL1诱导的足细胞损伤的近端途径，这是AAKD的一个中心机制。我们的 中心假说是，抑制JAK1和JAK2激酶将阻断APOL1诱导的足细胞损伤，并且 蛋白尿，从而减轻AAKD向ESKD的进展。这一假说是在 以申请人实验室产生的初步数据为基础。建议进行这项研究的理由是 AAKD有效治疗方法的发现将减少ESKD发病率的差异，即 ESKD护理，以及与ESKD相关的巨大生命损失-这是几乎同样重要的 女性的寿命损失与乳腺癌一样多，男性的寿命损失比结直肠癌更多。 在强劲的初步数据的指导下，这一假设将通过追求三个具体目标来检验：1)建立 Durham社区APOL1社区参与和翻译研究计划；2)执行试点 用于AAKD患者的临床可用的JAK1/2抑制剂的II期随机临床试验；以及3)进行 再生障碍性贫血患者诱导多能干细胞来源足细胞的体外临床试验 FSGS和HTN-CKD。我们的方法是创新的，因为它利用了一个创造性的社区 参与战略，以解决在临床试验中AA代表性不足的关键问题，同时 同时研究一种治疗AAKD的创新疗法的有效性和安全性。它还利用我们的 创新的iPod平台作为个性化治疗的工具。这项拟议的研究具有重要意义，因为它 预计将作为JAK1/2抑制剂治疗AAKD的未来III期试验的基础。网络的影响 AAKD的治疗包括减少ESKD的不同负担、死亡率和相关的财务成本 AAKD，这是NIDDK的优先事项。此外，由于它能够预测患者未来的临床 作为对药物的回应，iPod平台致力于将AAKD的个性化治疗从理论推进到现实。

Project Summary/Abstract Disparities in kidney health is an important long-standing problem in the US. African Americans (AAs) who represent 13% of U.S population, develop end stage kidney disease at 3.5-fold higher rates than European Americans, explaining why 31% of people with end stage kidney disease (ESKD) are AAs. Two protein coding mutations in the Apolipoprotein L1 (APOL1) gene are the causal drivers of 70% of this excess risk of ESKD in AAs. Despite the urgent need for treatment of APOL1-associated kidney disease (AAKD), there have not been any therapeutic trials specifically focused on AAKD. This need is compounded by severe underrepresentation of AAs in clinical trials. Until these needs are met, disparities in kidney health in the US will persist. Our long- term goal is to develop targeted therapies for the two most common forms of AAKD: APOL1-associated focal segmental glomerulosclerosis (FSGS) and hypertension-induced chronic kidney disease (HTN-CKD) in order to mitigate the disparate burden of ESKD among AAs. The objective of this particular application is to target a proximal pathway that drives APOL1-induced podocyte injury, which is a central mechanism of AAKD. Our central hypothesis is that inhibition of JAK1 and JAK2 kinases will block APOL1-induced podocyte injury, and proteinuria, and thereby mitigate progression of AAKD to ESKD. This hypothesis has been formulated on the basis of preliminary data produced in the applicant’s laboratories. The rationale for the proposed research is that discovery of an effective treatment for AAKD will reduce disparities in ESKD incidence, the high cost of ESKD care, and the enormous loss of lives associated with ESKD—which is responsible for nearly as much loss of life-years as breast cancer in women and more loss of life-years than colorectal cancer in men. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Build the Durham Community APOL1 Program for community engagement and translational research; 2) Perform a pilot phase II randomized clinical trial of a clinically available JAK1/2 inhibitor in patients with AAKD; and 3) Conduct an ex vivo clinical trial “in-a-dish” using induced pluripotent stem cell-derived podocytes (iPods) of AA patients with FSGS and HTN-CKD. Our approach is innovative because it leverages a creative community engagement strategy to addresses the critical problem of underrepresentation of AAs in clinical trials while simultaneously studying the efficacy and safety of an innovative treatment for AAKD. It also leverages our innovative iPod platform as a tool for individualized therapy. The proposed research is significant because it is expected to serve as the basis for a future phase III trial of JAK1/2 inhibitor as therapy for AAKD. The impact of therapy for AAKD includes reduction of the disparate burden of ESKD, mortality and financial cost associated with AAKD, which are priorities of NIDDK. Additionally, because of its ability to predict patient’s future clinical response to a drug, the iPod platform strives to advance personalized therapy of AAKD from theory to reality.