Journal
EMBO MOLECULAR MEDICINE
Volume 13, Issue 7, Pages -Publisher
WILEY
DOI: 10.15252/emmm.202013067
Keywords
alpha-ketoglutarate; Bicalutamide combination therapy; cysteamine; cystinosis; renal Fanconi syndrome
Categories
Funding
- Dutch Kidney Foundation [150KG19]
- Zon-MW [113301402]
- Netherlands Organization for Scientific Research [024.003.013]
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Through omics analysis, researchers identified alpha-ketoglutarate as a potential metabolite linking cystinosin loss to autophagy, apoptosis, and kidney proximal tubule impairment in cystinosis. Combining this insight with a drug screen, they discovered that a bicalutamide-cysteamine combination treatment could correct the phenotype of cystinotic kidney proximal tubule cells.
Nephropathic cystinosis is a severe monogenic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established renal proximal tubulopathy. Here, we developed a new therapeutic strategy by applying omics to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis. We identified alpha-ketoglutarate as a potential metabolite to bridge cystinosin loss to autophagy, apoptosis and kidney proximal tubule impairment in cystinosis. This insight combined with a drug screen revealed a bicalutamide-cysteamine combination treatment as a novel dual-target pharmacological approach for the phenotypical correction of cystinotic kidney proximal tubule cells, patient-derived kidney tubuloids and cystinotic zebrafish.
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