Open AccessCysteamine–bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis
Author(s) -
Jamalpoor Amer,
Gelder Charlotte AGH,
Yousef Yengej Fjodor A,
Zaal Esther A,
Berlingerio Sante P,
Veys Koenraad R,
Pou Casellas Carla,
Voskuil Koen,
Essa Khaled,
Ammerlaan Carola ME,
Rega Laura Rita,
Welle Reini EN,
Lilien Marc R,
Rookmaaker Maarten B,
Clevers Hans,
Klumperman Judith,
Levtchenko Elena,
Berkers Celia R,
Verhaar Marianne C,
Altelaar Maarten,
Masereeuw Rosalinde,
Janssen Manoe J
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202013067
Subject(s) - cystinosis , cysteamine , tubulopathy , lysosomal storage disease , kidney , cancer research , distal convoluted tubule , acute kidney injury , fanconi syndrome , medicine , endocrinology , chemistry , cystine , pharmacology , biochemistry , disease , reabsorption , cysteine , enzyme
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.