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Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis
Anna Taranta1, Mohamed A Elmonem2,3, Francesco Bellomo1
1Renal Diseases Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.
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.
Insights
Disulfiram (DSF) showed promise for nephropathic cystinosis by reducing cystine but caused growth issues in mice. Lower doses were ineffective and toxic, indicating DSF
Area of Science:
- Rare genetic diseases
- Lysosomal storage disorders
- Nephrology and molecular medicine
Background:
- Nephropathic cystinosis results from CTNS gene mutations, leading to cystine accumulation and organ damage.
- Current cysteamine therapy offers partial benefits, necessitating novel treatment strategies.
- Cellular dysfunctions in cystinosis include apoptosis, autophagy defects, and oxidative stress.
Purpose of the Study:
- To evaluate disulfiram (DSF), a drug repositioning candidate, as a potential therapeutic agent for nephropathic cystinosis.
- To assess the efficacy and toxicity of DSF in preclinical models of cystinosis.
Main Methods:
- In vitro assays confirmed DSF's cystine-depleting and anti-apoptotic effects.
- Ctns mutant mice were treated with DSF (200 mg/kg/day and 100 mg/kg/day) for varying durations.
- Cystinotic zebrafish larvae were used to assess DSF toxicity.
Main Results:
- High-dose DSF (200 mg/kg/day) reduced cystine and apoptosis in Ctns mice but caused growth impairment.
- Low-dose DSF (100 mg/kg/day) did not affect growth but failed to reduce cystine, led to premature death, and renal lesions.
- DSF exhibited enhanced toxicity in cystinotic mice and zebrafish compared to wild-type controls.
Conclusions:
- Disulfiram demonstrates dual effects in cystinosis models, with efficacy at doses causing toxicity.
- DSF's heightened toxicity in cystinotic cells suggests a potential therapeutic window challenge.
- Further research is needed to explore alternative DSF formulations or novel therapeutic targets for cystinosis.
