Abstract
Nephropathic cystinosis is a rare disease caused by mutations of the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. The disease is characterized by early-onset chronic kidney failure and progressive development of extra-renal complications related to cystine accumulation in all tissues. At the cellular level, several alterations have been demonstrated, including enhanced apoptosis, altered autophagy, defective intracellular trafficking, and cell oxidation, among others. Current therapy with cysteamine only partially reverts some of these changes, highlighting the need to develop additional treatments. Among compounds that were identified in a previous drug-repositioning study, disulfiram (DSF) was selected for in vivo studies. The cystine depleting and anti-apoptotic properties of DSF were confirmed by secondary in vitro assays and after treating Ctns-/- mice with 200 mg/kg/day of DSF for 3 months. However, at this dosage, growth impairment was observed. Long-term treatment with a lower dose (100 mg/kg/day) did not inhibit growth, but failed to reduce cystine accumulation, caused premature death, and did not prevent the development of renal lesions. In addition, DSF also caused adverse effects in cystinotic zebrafish larvae. DSF toxicity was significantly more pronounced in Ctns-/- mice and zebrafish compared to wild-type animals, suggesting higher cell toxicity of DSF in cystinotic cells.
Highlights
Nephropathic cystinosis (NC) is an inherited metabolic disease secondary to mutations in the CTNS gene, which encodes for cystinosin, a cystine proton symporter allowing efflux of cystine from lysosomes [? ]
Kidney damage is characterized in part by increased apoptosis of proximal tubular cells in mice [? ], confirming previous in vitro studies showing that cystinotic cells are more sensitive to apoptotic stimuli [? ? ]
Cysteamine was approved for the treatment of NC in the 1990s, and allows cystine clearance from lysosomes through the formation of a mixed cysteine–cysteamine disulfide that can exit lysosomes through the PQLC2 transporter [? ]
Summary
Nephropathic cystinosis (NC) is an inherited metabolic disease secondary to mutations in the CTNS gene, which encodes for cystinosin, a cystine proton symporter allowing efflux of cystine from lysosomes [? ]. The majority of patients progress to end-stage kidney disease in the second or third decade of life [? ]. In order to identify new molecules that can improve the treatment of patients with NC, two drug screenings were performed using conditionally immortalized human cystinotic proximal tubule cells [? ]. A high throughput screening based on cell cystine concentration identified 24 compounds that reduced cystine content by >50%. ]. We combined results from these two screenings, and identified disulfiram (DSF) as a potential treatment for cystinosis. We report the results of in vitro and in vivo studies assessing the efficacy of DSF in cystinotic human proximal tubule epithelial cells, mice, and zebrafish. Our results confirm the cystine-depleting and anti-apoptotic effects of DSF, but show significant toxicity that is enhanced in cystinotic animal models
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