JAK-STAT Inhibition to Reduce Racial Disparities in Kidney Disease

项目总结/文摘

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.