Thursday, November 21, 2024
11/21/2024
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.
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