Nephropathic/infantile cystinosis, characterized by the development of renal Fanconi syndrome and glomerular dysfunction, results in end-stage renal disease (ESRD) by 10 years of age, extendable to the second decade of life with cystine depletion therapy, Cysteamine. Nevertheless, persistent Fanconi and progressive renal failure remains a reality for these individuals, despite robust adherence with cystine depletion therapies. In this proposal, we seek to greatly improve the treatment of cystinosis by advancing a more potent combination therapy based on cysteamine and Astaxanthin (ATX). Previously we showed that ATP6V0A1 plays a crucial role in cystinosis-associated renal pathology and among other antioxidants, ATX specifically upregulated ATP6V0A1, improved autophagosome turnover (or reduce autophagy) and mitochondrial integrity. This proposal is the required next step, where we will study the effect of ATX on renal Fanconi in Ctns-/- rat model to clarify ATX’s utility in clinical settings. In this pre-clinical study, we will test if the treatment of our Ctns-/- rats with a combination therapy of Cysteamine and ATX will be more renal-protective than cysteamine treatment alone. This work will lay the groundwork for moving combination treatment, Cysteamine and ATX, into clinical trials.
