Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

Taranta, Anna; Elmonem, Mohamed A.; Bellomo, Francesco; Leo, Ester De; Boenzi, Sara; Janssen, Manoe J.; Jamalpoor, Amer; Cairoli, Sara; Pastore, Anna; Stefanis, Cristiano De; Colucci, Manuela; Rega, Laura Rita; Giovannoni, Isabella; Francalanci, Paola; Heuvel, Lambertus P. van den; Dionisi‐Vici, Carlo; Goffredo, Bianca Maria; Masereeuw, Rosalinde; Levtchenko, Elena; Emma, Francesco

doi:10.3390/cells10123294

Cited by 8 publications

(5 citation statements)

References 36 publications

(36 reference statements)

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“…( 27 ). The renal Fanconi syndrome was significantly milder, compared with that of previous reports ( 28 ); however, the causes of this discrepancy are currently under investigation in our laboratory. This cystinotic mouse model has been widely used to obtain key insights in the pathophysiology of cystinosis ( 9 , 26 , 29–32 ) and to develop new therapeutic strategies ( 30 , 33–35 ).…”

Section: Discussioncontrasting

confidence: 65%

Genistein improves renal disease in a mouse model of nephropathic cystinosis: a comparison study with cysteamine

Leo

Taranta

Raso

et al. 2022

Human Molecular Genetics

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Background Cysteamine is currently the only therapy for nephropathic cystinosis. It significantly improves life expectancy and delays progression to end-stage kidney disease, however, it cannot prevent it. Unfortunately, compliance to therapy is often weak, particularly during adolescence. Therefore, finding better treatments is a priority in the field of cystinosis. Previously, we found that genistein, an isoflavone particularly enriched in soy, can revert part of the cystinotic cellular phenotype that is not sensitive to cysteamine in vitro. Methods To test the effects of genistein in vivo, we fed 2-month-old wild type and Ctns−/− female mice with either a control diet, a genistein-containing diet or a cysteamine-containing diet for 14 months. Results Genistein (160 mg/kg/day) did not affect the growth of the mice or hepatic functionality. Compared with untreated mice at 16 months, Ctns−/− mice fed with genistein had lower cystine concentrations in their kidneys, reduced formation of cystine crystals, a smaller number of LAMP1-positive structures, and an overall better-preserved parenchymal architecture. Cysteamine (400 mg/kg/day) was efficient in reverting the lysosomal phenotype and in preventing the development of renal lesions. Conclusions These preclinical data indicate that genistein ameliorates kidney injury resulting from cystinosis with no side effects. Genistein therapy represents a potential treatment to improve the outcome for patients with cystinosis.

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Section: Discussioncontrasting

confidence: 65%

Genistein improves renal disease in a mouse model of nephropathic cystinosis: a comparison study with cysteamine

Leo

Taranta

Raso

et al. 2022

Human Molecular Genetics

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“…They produced a list of additional potential drugs acting with the exact mechanisms of action. In a follow-up paper, the same authors investigated the effects of DSF on animal models using mice and zebrafish [ 25 ]. Notwithstanding the decades of DSF application, in particular, to treat chronic alcoholism, prolonged exposure to the drug resulted in markedly increased toxicity for cystinotic animals.…”

Section: Shooting At Random: the Valuable Results Of High-throughput ...mentioning

confidence: 99%

“…A workflow detailing the entire process is visible in Figure 1 , and papers are synthesized in Table 1 . Searching for these articles’ DOIs on UniProt returned two hits [ 24 , 25 ] linked to proteins not associated with any OMIM or OrphaNet on UniProtKB, while searching the publication DOIs on OMIM using the “ref_doi’’ key yielded no results. Furthermore, ~30% of the articles were not associated with any LSD-related Medical Subject Headings (MeSHs), and only five of those 27 documents were annotated on PubMed with the Drug Repositioning MeSH.…”

Section: Drug Repositioning For Lysosomal Storage Disorders: Still a ...mentioning

confidence: 99%

Drug Repurposing and Lysosomal Storage Disorders: A Trick to Treat

Hay Mele,

Rossetti,

Cubellis

et al. 2024

Genes

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Rare diseases, or orphan diseases, are defined as diseases affecting a small number of people compared to the general population. Among these, we find lysosomal storage disorders (LSDs), a cluster of rare metabolic diseases characterized by enzyme mutations causing abnormal glycolipid storage. Drug repositioning involves repurposing existing approved drugs for new therapeutic applications, offering advantages in cost, time savings, and a lower risk of failure. We present a comprehensive analysis of existing drugs, their repurposing potential, and their clinical implications in the context of LSDs, highlighting the necessity of mutation-specific approaches. Our review systematically explores the landscape of drug repositioning as a means to enhance LSDs therapies. The findings advocate for the strategic repositioning of drugs, accentuating its role in expediting the discovery of effective treatments. We conclude that drug repurposing represents a viable pathway for accelerating therapeutic discovery for LSDs, emphasizing the need for the careful evaluation of drug efficacy and toxicity in disease-specific contexts.

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“…Diffusion through lysosomal membranes is typically restricted to molecules of mass less than 200-230 daltons [31]. Also, Taranta et al [30] reported the cystine-depleting and anti-apoptotic properties of the disulfide, disulfiram, confirmed by secondary in vitro assays and after treating Ctns-/-mice with 200 mg/kg/day of disulfiram for 3 months. However, at this dosage, growth impairment was observed and 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.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of NACA and diNACA in human cystinosis fibroblast cell cultures as potential treatments for cystinosis

Hector

Cairns

Wall³

2022

Orphanet J Rare Dis

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Background Cystinosis is a rare autosomal recessive lysosomal storage disease, associated with high morbidity and mortality. Mutations in the CTNS gene disable a membrane protein responsible for the transport of cystine out of the lysosome. Loss of transporter function leads to intralysosomal cystine accumulation and long-term damage to various tissues and organs, including the kidneys, eyes, liver, muscles, pancreas, and brain. The only cystine-depletion therapy for treatment of cystinosis is cysteamine which requires frequent administration of high doses and often causes gastrointestinal pain as well as pungent sulfurous odor in patients. The current in vitro study evaluated antioxidants, N-acetylcysteine amide (NACA; NPI-001) and (2R,2R′)-3,3′-disulfanediyl bis(2-acetamidopropanamide) (diNACA; NPI-002), as potential treatments for cystinosis. Methods Cytotoxicity of cysteamine, NACA and diNACA was evaluated in cultured human cystinotic fibroblasts (HCFs). HCFs were cultured in 96 well plates incubated for 0–72 h in the presence of 25, 50 or 75 μM each of either cysteamine, NACA or diNACA along with an untreated control. Media was removed and cell viability assessed. Next, cystine-depleting activities of cysteamine, NACA and diNACA were screened in HCFs cell culture utilizing an inexpensive, proven colorimetric assay. HCFs were seeded and allowed to reach approximately 80% confluence before the addition of the test articles: 50 μM of either cysteamine, NACA or diNACA in media along with an untreated control. HCFs were incubated, harvested, and cystine was reduced to cysteine, the concentration of which was then determined per quantity of protein compared to a cysteine standard. Statistically significant cystine depletion was determined by paired t-test versus untreated control (p < 0.05). Results Neither cysteamine, NACA nor diNACA at 25, 50 or 75 μM caused cytotoxicity in HCFs. Treatment with all tested concentrations (25, 50 or 75 µM) of either NACA or diNACA at 48 or 72 h resulted in statistically significant increases in cell viability, relative to untreated control, whereas the higher concentrations (50 or 75 µM) of cysteamine achieved statistical significance at both timepoints but not the lowest concentration (25 µM). All test articles depleted cystine from HCFs compared to control. NACA depletion of cystine was statistically superior to cysteamine at 6, 24 and 48 h and numerically greater at 72 h. DiNACA depletion of cystine was statistically superior to cysteamine at 6 and 48 h, slightly numerically greater at 24 h and slightly less at 72 h. Conclusions NACA and diNACA were non cytotoxic to HCFs and significantly increased cell viability. Cystine reduction was determined as percent of control after incubation with 50 µM of NACA, diNACA or cysteamine in HCFs cell culture for 6, 24, 48 and 72 h. Of the three test articles, NACA exhibited most rapid and greatest potency in cystine reduction. Rank order potency for cystine reduction over time was observed, NACA > diNACA ≥ cysteamine. Therefore, further study of NACA and diNACA as potential treatments for cystinosis is warranted.

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Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

Cited by 8 publications

References 36 publications

Genistein improves renal disease in a mouse model of nephropathic cystinosis: a comparison study with cysteamine

Genistein improves renal disease in a mouse model of nephropathic cystinosis: a comparison study with cysteamine

Drug Repurposing and Lysosomal Storage Disorders: A Trick to Treat

Evaluation of NACA and diNACA in human cystinosis fibroblast cell cultures as potential treatments for cystinosis

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