Cysteamine–bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis

Jamalpoor, Amer; Gelder, Charlotte Agh van; Yengej, Fjodor A. Yousef; Zaal, Esther A.; Berlingerio, Sante Princiero; Veys, Koenraad; Casellas, Carla Pou; Voskuil, Koen; Essa, Khaled; Ammerlaan, Carola; Rega, Laura Rita; Welle, Reini En van der; Lilien, Marc R.; Rookmaaker, Maarten B.; Klumperman, Judith; Levtchenko, Elena; Berkers, Celia R.; Verhaar, Marianne C.; Altelaar, Maarten; Masereeuw, Rosalinde; Janssen, Manoe J.

doi:10.15252/emmm.202013067

Cited by 31 publications

(42 citation statements)

References 70 publications

(102 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After treatment with 10 µM DSF, cells were incubated with CellROX Green Reagent (Thermo Fisher Scientific) for 30 min at room temperature and reactive oxygen species (ROS) were measured by live cell flow cytometry. GSH and GSSG levels were analyzed as described by Jamalpoor et al, who have performed extensive metabolomic investigations in the same cell conditions [ 12 ].…”

Section: Methodsmentioning

confidence: 99%

Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

Taranta

Elmonem

Bellomo

et al. 2021

Cells

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Methodsmentioning

confidence: 99%

Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

Taranta

Elmonem

Bellomo

et al. 2021

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

“…Three ciPTECs lines were used for this study: the healthy control ciPTEC, CTNS WT (also referred to as ciPTEC14.4 in previous literature) [ 24 ], and two cystinotic models ciPTEC CTNS Patient (ciPTEC46.2) [ 34 ] and ciPTEC CTNS −/− . CTNS −/− is an isogenic immortalized cell line derived from ciPTEC14.4 and generated in-house previously [ 9 ], which harbors a biallelic mutation in the exon 4 of the CTNS gene. The ciPTEC46.6 (referred to as “Patient”) is an immortalized cell line derived from a urine sample of a cystinotic patient harboring a 57 kb deletion which includes the first 10 exons of the CTNS gene.…”

Section: Methodsmentioning

confidence: 99%

“…One of the first manifestations of cystinosis is the clinical presentation of renal Fanconi syndrome, characterized by a severe proximal tubule cell dysfunction at early stages of the disease, which results in a total loss of integrity of the proximal tubule [ 7 ]. Great efforts have been made to elucidate further the underlying pathological mechanisms of nephropathic cystinosis that revealed several hallmarks beyond cystine accumulation, including impaired autophagy, mTOR activation, disrupted vesicle dynamics (lysosomes-autophagosomes interactions), mitochondrial impairment, reactive oxygen species (ROS), and increased cell stress [ 8 , 9 , 10 , 11 , 12 , 13 ]. Despite clinical improvements in prognosis, there is, as of yet, no curative therapy available for cystinosis.…”

Section: Introductionmentioning

confidence: 99%

“…While valuable, their restricted availability and lack of capacity to stay in culture for more than a few passages urged researchers to immortalize primary cultures following different strategies. An example forms the ciPTEC (conditionally immortalized proximal tubule epithelial cells) [ 24 ], a model that has been shown to be particularly useful for investigating the molecular mechanisms affected in nephropathic cystinosis [ 9 ]. However, individual variability and the lack of a healthy control with the same genetic background as the cystinotic donor are major hurdles in pinpointing the molecular mechanism associated with the disease.…”

Section: Introductionmentioning

confidence: 99%

“…However, individual variability and the lack of a healthy control with the same genetic background as the cystinotic donor are major hurdles in pinpointing the molecular mechanism associated with the disease. To overcome this issue, recent studies have created isogenic cell lines using CRISPR-Cas by knocking out the CTNS gene [ 9 , 10 ]. In addition, advancements in the culture of primary cells obtained from patients’ urine now allow prolonged in vitro expansion in the form of adult organoids.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Bioengineered Cystinotic Kidney Tubules Recapitulate a Nephropathic Phenotype

Garví

Masereeuw

Janssen

2022

Cells

Self Cite

View full text Add to dashboard Cite

Nephropathic cystinosis is a rare and severe disease caused by disruptions in the CTNS gene. Cystinosis is characterized by lysosomal cystine accumulation, vesicle trafficking impairment, oxidative stress, and apoptosis. Additionally, cystinotic patients exhibit weakening and leakage of the proximal tubular segment of the nephrons, leading to renal Fanconi syndrome and kidney failure early in life. Current in vitro cystinotic models cannot recapitulate all clinical features of the disease which limits their translational value. Therefore, the development of novel, complex in vitro models that better mimic the disease and exhibit characteristics not compatible with 2-dimensional cell culture is of crucial importance for novel therapies development. In this study, we developed a 3-dimensional bioengineered model of nephropathic cystinosis by culturing conditionally immortalized proximal tubule epithelial cells (ciPTECs) on hollow fiber membranes (HFM). Cystinotic kidney tubules showed lysosomal cystine accumulation, increased autophagy and vesicle trafficking deterioration, the impairment of several metabolic pathways, and the disruption of the epithelial monolayer tightness as compared to control kidney tubules. In particular, the loss of monolayer organization and leakage could be mimicked with the use of the cystinotic kidney tubules, which has not been possible before, using the standard 2-dimensional cell culture. Overall, bioengineered cystinotic kidney tubules recapitulate better the nephropathic phenotype at a molecular, structural, and functional proximal tubule level compared to 2-dimensional cell cultures.

show abstract

Organs-on-chip technology: a tool to tackle genetic kidney diseases

et al. 2022

Self Cite

View full text Add to dashboard Cite

Chronic kidney disease (CKD) is a major healthcare burden that takes a toll on the quality of life of many patients. Emerging evidence indicates that a substantial proportion of these patients carry a genetic defect that contributes to their disease. Any effort to reduce the percentage of patients with a diagnosis of nephropathy heading towards kidney replacement therapies should therefore be encouraged. Besides early genetic screenings and registries, in vitro systems that mimic the complexity and pathophysiological aspects of the disease could advance the screening for targeted and personalized therapies. In this regard, the use of patient-derived cell lines, as well as the generation of disease-specific cell lines via gene editing and stem cell technologies, have significantly improved our understanding of the molecular mechanisms underlying inherited kidney diseases. Furthermore, organs-on-chip technology holds great potential as it can emulate tissue and organ functions that are not found in other, more simple, in vitro models. The personalized nature of the chips, together with physiologically relevant read-outs, provide new opportunities for patient-specific assessment, as well as personalized strategies for treatment. In this review, we summarize the major kidney-on-chip (KOC) configurations and present the most recent studies on the in vitro representation of genetic kidney diseases using KOC-driven strategies.

show abstract

Cysteamine–bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis

Cited by 31 publications

References 70 publications

Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

Bioengineered Cystinotic Kidney Tubules Recapitulate a Nephropathic Phenotype

Organs-on-chip technology: a tool to tackle genetic kidney diseases

Contact Info

Product

Resources

About