JAK-STAT Inhibition to Reduce Racial Disparities in Kidney Disease

JAK-STAT 抑制可减少肾脏疾病的种族差异

• 批准号: 10491289
• 负责人: Opeyemi Ayodeji Olabisi
• 金额: $ 67.19万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491289
• 关键词: APOL1 gene; Address; African; African American; African American population; Albumins; American; Apolipoproteins; Biopsy; Caring; Cells; Chronic Kidney Failure; Church; Clinical; Clinical Trials; Code; Colorectal Cancer; Communities; Creatinine; Data; Development; Diagnosis; Disease; End stage renal failure; Enrollment; European; Failure; Financial cost; Focal Segmental Glomerulosclerosis; Future; Genes; Genotype; Glomerular Filtration Rate; Goals; Health; Hemoglobin; Human; Hypertension; Incidence; Individual; Injury; Injury to Kidney; Interferon Type II; JAK1 gene; JAK2 gene; Kidney; Kidney Diseases; Laboratories; Life; Malaria; Mission; Mutation; Names; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Immunity; Nephrology; Outcome; Participant; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phase; Phosphotransferases; Placebos; Population; Potassium; Prediction of Response to Therapy; Proteins; Proteinuria; Public Health; Randomized; Randomized Clinical Trials; Research; Risk; Safety; Sickle Hemoglobin; Signal Transduction; Testing; Therapeutic Trials; Translational Research; Trypanosoma; Validation; Variant; Woman; base; causal variant; clinical predictors; community engagement; cost; disparity reduction; effective therapy; efficacy study; efficacy testing; glomerular filtration; health disparity; high risk; in vivo; individualized medicine; induced pluripotent stem cell; inhibitor; innovation; malignant breast neoplasm; men; mortality; novel; patient oriented research; personalized medicine; personalized therapeutic; phase III trial; podocyte; predictive tools; primary endpoint; programs; protective effect; racial disparity; randomized trial; response; risk variant; safety assessment; screening; targeted treatment; theories; tool; treatment response; urinary

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.

项目总结/摘要 肾脏健康的差异是美国长期存在的重要问题。非裔美国人（AAs） 占美国人口的13%，终末期肾病的发病率是欧洲人的3.5倍 这解释了为什么31%的终末期肾病（ESKD）患者是AA。两个蛋白质编码 载脂蛋白L1（APOL 1）基因突变是70%的ESKD过度风险的因果驱动因素， 原子吸收法尽管迫切需要治疗APOL 1相关肾病（AAKD），但目前还没有 任何专门针对AAKD的治疗试验。代表性严重不足，加剧了这一需求 临床试验中的AA。在这些需求得到满足之前，美国肾脏健康的差距将持续存在。我们长久以来- 长期目标是为两种最常见的AAKD形式开发靶向治疗：APOL 1相关的局灶性 节段性肾小球硬化（FSGS）和高血压引起的慢性肾脏病（HTN-CKD） 以减轻认可机构之间ESKD的不同负担。此特定应用程序的目标是针对 近端通路驱动APOL 1诱导的足细胞损伤，这是AAKD的中心机制。我们 中心假设是JAK 1和JAK 2激酶的抑制将阻断APOL 1诱导的足细胞损伤， 蛋白尿，从而减轻AAKD向ESKD的进展。这一假设是根据 根据申请人实验室提供的初步数据。拟议研究的基本原理是 AAKD有效治疗的发现将减少ESKD发病率的差异， ESKD护理，以及与ESKD相关的巨大生命损失-这几乎是同样多的责任 女性乳腺癌的生命年损失，男性结肠直肠癌的生命年损失更多。 在强有力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 达勒姆社区APOL 1计划，用于社区参与和转化研究; 2）进行试点 在AAKD患者中进行临床可用的JAK 1/2抑制剂的II期随机临床试验;和3）进行 使用AA患者的诱导多能干细胞衍生的足细胞（iPod）的离体临床试验“在培养皿中” FSGS和HTN-CKD。我们的方法是创新的，因为它利用了创造性的社区 参与战略，以解决临床试验中AA代表性不足的关键问题， 同时研究AAKD创新治疗的有效性和安全性。它还利用了我们的 创新的iPod平台作为个性化治疗的工具。这项研究之所以重要，是因为 预计将作为JAK 1/2抑制剂作为AAKD治疗的未来III期试验的基础。的影响 AAKD的治疗包括减少ESKD的不同负担、死亡率和相关的经济成本。 与AAKD，这是NIDDK的优先事项。此外，由于其预测患者未来临床表现的能力， iPod平台致力于将AAKD的个性化治疗从理论推进到现实。