NTC study

Infantile cystinosis is a rare disease secondary to mutations in the CTNS gene, which cause early onset renal failure followed by numerous symptoms related to progressive lysosomal cystine accumulation in all cells of the body and to alteration of other metabolic pathways that have been elucidated in recent years. In this application, four different groups with extensive experience in the fields of cystinosis, pharmacology/toxicology and cell-based therapies, and with a track record of successful collaboration between each other, propose to join forces to develop new therapeutic approaches using cell and animal models that have been developed for the most part in their laboratories. The application is divided in 3 specific aim. In specific aim #1, we propose to test on zebrafish and mouse models of cystinosis a selective number of compounds that have been identified by screening a 1200 molecule library for drugs that reduce cystine content in cultured cystinotic proximal tubular cells. In specific aim #2, we propose to perform two additional high throughput screenings using different readouts, namely decreased activation of the inflammosome and correction of the phenotype of Ctns -/- zebrafish embryos. These studies will be complemented by toxicology and pharmacology experiments to test the safety and therapeutic index of candidate drugs. Finally, in specific aim #3, we propose to test the capacity of human CD24(+)/CD133(+) renal progenitor cells to efficiently repopulate renal proximal tubular cells and to correct the renal phenotype of cystinotic NOD/SCID mice.