Cysteamine–bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis

Amer Jamalpoor, Charlotte A.G.H. van Gelder, Fjodor A. Yousef Yengej, Esther A. Zaal, Sante P. Berlingerio, Koenraad R. Veys, Carla Pou Casellas, Koen Voskuil, Khaled Essa, Carola M.E. Ammerlaan, Laura Rita Rega, Reini E.N. van der Welle, Marc R. Lilien, Maarten B. Rookmaaker, Hans Clevers, Judith Klumperman, Elena Levtchenko, Celia R. Berkers, Marianne C. Verhaar, Maarten AltelaarRosalinde Masereeuw, Manoe J. Janssen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Article numbere13067
Pages (from-to)1-20
Number of pages20
JournalEMBO Molecular Medicine
Issue number7
Publication statusPublished - 7 Jul 2021


  • alpha-ketoglutarate
  • Bicalutamide combination therapy
  • cysteamine
  • cystinosis
  • renal Fanconi syndrome


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