Unravelling the role of PAX2 mutations in human Focal Segmental Glomerulosclerosis

Focal Segmental Glomerulosclerosis is a kidney lesion that mainly affects the podocytes, specialized cells responsible for the kidney capacity to eliminate waste solutes into urines, while retaining in the blood large molecules such as albumin. In patients with Focal Segmental Glomerulosclerosis the renal filter becomes incompetent resulting in albumin loss in the urines and development of end stage renal failure. No specific treatment is available. Studies in familial forms of Focal Segmental Glomerulosclerosis identified genetic defects that affect proteins involved in podocyte structure and development. Recently, a novel alteration in the gene encoding PAX2, a protein involved in kidney development, was found in two related patients who referred to the Clinical Research Center for Rare Diseases of the Mario Negri Institute. The aim of this project is to understand the molecular mechanisms by which the PAX2 genetic defect affects podocyte maturation and function, leading to Focal Segmental Glomerulosclerosis. To this purpose, we will use an innovative protocol to obtain podocytes without performing renal biopsy. Patients’ adult blood cells will be reprogrammed to an embryonic-like pluripotent state from which they will be differentiated into podocytes. The structure and function of such podocytes and their ability to properly mature into an embryonic kidney tissue will be studied. Genetic defect will be corrected in patient’s induced-pluripotent stem cells by gene-editing and the ability of edited cells to differentiate into podocytes with normal structure and function will be verified. Results of this project will enable to identify molecular targets for future clinical trials with clear benefit to patients with genetic forms of Focal Segmental Glomerulosclerosis. These findings can be extended to any other mutation identified in these patients, leading to a significant advance beyond the current knowledge of Focal Segmental Glomerulosclerosis pathogenesis.