New Therapeutic Leads for Proteinuric Kidney Diseases

蛋白尿性肾病的新治疗方法

• 批准号: 10525660
• 负责人: Weining Lu
• 金额: $ 26.7万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525660
• 关键词: Actins; Adhesions; Adult; Affect; Albumins; Albuminuria; Animal Model; Biological Response Modifier Therapy; Biopsy Specimen; Birth; Boston; Caring; Chimeric Proteins; Chronic Kidney Failure; Cohort Studies; Collaborations; Data; Dialysis procedure; Disease Progression; Dominant-Negative Mutation; Embryo; Focal Adhesions; Focal Segmental Glomerulosclerosis; Foot Process; Gel; Gene Proteins; Goals; Human; Injury; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Lead; Length; Ligands; Medical; Metanephric Diverticulum; Monoclonal Antibodies; Morbidity - disease rate; Mus; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Outcome; Pathway interactions; Patients; Permeability; Persons; Phase II Clinical Trials; Play; Population; Positioning Attribute; Proteins; Proteinuria; Reflux; Resistance; Risk Factors; Role; Safety; Serum Albumin; Side; Signal Pathway; Signal Transduction; Steroids; Structure; Therapeutic; Toxic effect; Transcript; Urinary tract; Urine; Validation; Vascularization; Vesico-Ureteral Reflux; congenital anomalies of the kidney; cost; density; drug development; early detection biomarkers; efficacy testing; glomerular basement membrane; glomerular filtration; inhibitor; innovation; kidney biopsy; mortality; nephrin; nephrogenesis; new therapeutic target; non-muscle myosin; novel; novel therapeutics; phase II trial; podocyte; polymerization; pre-clinical; prevent; protein expression; public health relevance; receptor; safety testing; slit diaphragm

Modified Project Summary/Abstract The primary goal of this project is to validate a novel therapeutic lead targeting the ROBO/SLIT signaling pathway in pre-clinical animal models and human kidney biopsy samples of proteinuric kidney disease. ROBO (including ROBO1/2) are receptors for SLIT ligands (including SLIT2/3). ROBO/SLIT pathway has been shown to play an essential role during early kidney development. Mutations in either ROBO1, ROBO2, or SLIT2 cause congenital anomalies of the kidney and urinary tract (CAKUT) and vesicoureteral reflux (VUR) in humans and mice. We also discovered a novel, unexpected function of the ROBO/SLIT pathway in mature kidney podocytes, which acts as a negative regulator on nephrin to inhibit nephrin-induced actin polymerization and destabilizes podocyte adhesion and attachment to the glomerular basement membrane (GBM) by inhibiting nonmuscle myosin IIA (NM-IIA) activity. In addition, we found that inhibiting the ROBO/SLIT pathway genetically in animal models of podocyte injury and podocytopathies reduced albuminuria by enhanced podocyte adhesion, which maintained the podocyte foot process, slit-diaphragm ultrastructure, and the podocyte buttress force. These data suggest that the ROBO/SLIT pathway is a novel drug target for podocyte injury and podocyte protection. Blocking the ROBO/SLIT pathway may lead to potentially novel therapies for patients with podocyte injury and albuminuria. Indeed, in collaboration with Pfizer, we generated several novel therapeutic leads inhibiting the ROBO/SLIT pathway. One of the novel therapeutic leads, PF-06730512, significantly reduced albuminuria in pre-clinical proteinuric animal models. This PF-06730512 is currently in a phase 2 clinical trial for patients with FSGS. The latest interim analysis of this phase 2 trial showed a significant proteinuria reduction in steroid/treatment-resistant FSGS patients after 12 weeks of PF-06730512 treatment. In this special NIDDK early-stage preclinical therapeutic leads validation project, we plan to test the efficacy and safety of one additional novel therapeutic lead inhibiting ROBO1 and ROBO2 receptors that we generated in collaboration with Pfizer in pre-clinical animal models of proteinuric kidney disease and CAKUT (Aim 1 and Aim 2). In addition, we plan to validate ROBO/SLIT pathway gene/protein expressions in kidney biopsy samples that have been collected from patients with proteinuric kidney disease (Aim 3). This project will support the indication expansion of the ROBO/SLIT inhibitors with different mechanisms of action to further increase the overall likelihood of a successful drug development project targeting the ROBO/SLIT pathway for proteinuric kidney disease.

修改后的项目摘要/摘要 该项目的主要目标是在蛋白尿肾病的临床前动物模型和人肾活检样本中验证一种针对 ROBO/SLIT 信号通路的新型治疗先导药物。 ROBO（包括ROBO1/2）是SLIT配体（包括SLIT2/3）的受体。 ROBO/SLIT 通路已被证明在早期肾脏发育过程中发挥着重要作用。 ROBO1、ROBO2 或 SLIT2 的突变会导致人类和小鼠先天性肾脏和尿路异常 (CAKUT) 以及膀胱输尿管反流 (VUR)。我们还发现了成熟肾足细胞中 ROBO/SLIT 途径的一种新的、意想不到的功能，它作为去氧肾上腺素的负调节因子，抑制去氧肾上腺素诱导的肌动蛋白聚合，并通过抑制足细胞粘附和附着到肾小球基底膜 (GBM) 来破坏足细胞的稳定性。非肌肉肌球蛋白 IIA (NM-IIA) 活性。此外，我们发现，在足细胞损伤和足细胞病的动物模型中，通过基因抑制 ROBO/SLIT 通路，可以通过增强足细胞粘附来减少蛋白尿，从而维持足细胞足突、狭缝隔膜超微结构和足细胞支撑力。这些数据表明 ROBO/SLIT 通路是足细胞损伤和足细胞保护的新药物靶点。阻断 ROBO/SLIT 通路可能会为足细胞损伤和蛋白尿患者带来潜在的新疗法。事实上，我们与辉瑞合作，产生了几种抑制 ROBO/SLIT 通路的新型治疗先导化合物。其中一种新型治疗药物 PF-06730512 可显着减少临床前蛋白尿动物模型中的蛋白尿。 PF-06730512 目前正处于针对 FSGS 患者的 2 期临床试验中。该 2 期试验的最新中期分析显示，在 PF-06730512 治疗 12 周后，类固醇/治疗耐药 FSGS 患者的蛋白尿显着减少。在这个特殊的 NIDDK 早期临床前治疗先导验证项目中，我们计划测试我们与辉瑞合作在蛋白尿肾病和CAKUT（目标 1 和目标 2）。此外，我们计划验证从蛋白尿肾病患者收集的肾活检样本中 ROBO/SLIT 通路基因/蛋白的表达（目标 3）。该项目将支持具有不同作用机制的 ROBO/SLIT 抑制剂的适应症扩展，以进一步增加针对蛋白尿肾病的 ROBO/SLIT 途径药物开发项目成功的总体可能性。