Research of Therapeutic Targets in the Frame of Nephronophthisis and Renal Associated Ciliopathies

Overview

Nephronophthisis (NPH) is an autosomal recessive, genetically heterogeneous disease, with mutations identified in over 20 genes (notably NPHP1 and NPHP4). These genetic defects are associated with reduced urine concentration, chronic tubulointerstitial nephritis, etc., and progress to end-stage renal failure before the age of 20. Nephronophthisis may occur as an isolated pathology, but is also often associated with various extrarenal symptoms. NPHP genes account for around 50% of the genes responsible for NPH. No effective treatment is available to date. Studying NPHP proteins and associated signaling pathways could help identify how to circumvent the problems of protein distribution and therapeutic mRNA, and could be applicable to a broad set of NPHP mutations. To this end, Dr. Saunier's laboratory at Institut Imagine has recently identified approved drugs that correct some of the ciliary and epithelial defects found in cells with NPHP mutations.

Nephronophthisis (NPH) is an autosomal recessive, genetically heterogeneous disease, with mutations identified in over 20 genes (notably NPHP1 and NPHP4). These genetic defects are associated with reduced urine concentration, chronic tubulointerstitial nephritis, etc., and progress to end-stage renal failure before the age of 20. Nephronophthisis may occur as an isolated pathology, but is also often associated with various extrarenal symptoms such as retinal dystrophy, cerebellar vermis hypoplasia, skeletal dysmorphisms and/or situs/inversus. These disorders overlap phenotypically, genetically and functionally. All are thought to result from defective ciliary signaling and are classified as renal ciliopathies. NPHP genes account for around 50% of the genes responsible for NPH. No effective treatment is available to date. One possible therapeutic approach is to replace the defective protein; but delivery of recombinant proteins or mRNA to renal tubular cells is not currently feasible. However, each NPHP protein participates in numerous intracellular signalling pathways involving cilia functions. Studying NPHP proteins and associated signaling pathways could help identify how to circumvent the problems of protein distribution and therapeutic mRNA, and could be applicable to a broad set of NPHP mutations. To this end, Dr. Saunier's laboratory at Institut Imagine has recently identified approved drugs that correct some of the ciliary and epithelial defects found in cells with NPHP mutations. The global research project of which this protocol is a part seeks to identify new specific targets and develop new therapeutic agents against these targets for the treatment of NPH and other ciliopathies.