PUBLICATION
Cysteamine-bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis
- Authors
- Jamalpoor, A., van Gelder, C.A., Yousef Yengej, F.A., Zaal, E.A., Berlingerio, S.P., Veys, K.R., Pou Casellas, C., Voskuil, K., Essa, K., Ammerlaan, C.M., Rega, L.R., van der Welle, R.E., Lilien, M.R., Rookmaaker, M.B., Clevers, H., Klumperman, J., Levtchenko, E., Berkers, C.R., Verhaar, M.C., Altelaar, M., Masereeuw, R., Janssen, M.J.
- ID
- ZDB-PUB-210625-10
- Date
- 2021
- Source
- EMBO Molecular Medicine 13(7): e13067 (Journal)
- Registered Authors
- Keywords
- Bicalutamide combination therapy, alpha-ketoglutarate, cysteamine, cystinosis, renal Fanconi syndrome
- MeSH Terms
-
- Amino Acid Transport Systems, Neutral*/genetics
- Anilides
- Animals
- Cysteamine
- Cystinosis*/drug therapy
- Humans
- Nitriles
- Phenotype
- Tosyl Compounds
- Zebrafish
- PubMed
- 34165243 Full text @ EMBO Mol. Med.
Citation
Jamalpoor, A., van Gelder, C.A., Yousef Yengej, F.A., Zaal, E.A., Berlingerio, S.P., Veys, K.R., Pou Casellas, C., Voskuil, K., Essa, K., Ammerlaan, C.M., Rega, L.R., van der Welle, R.E., Lilien, M.R., Rookmaaker, M.B., Clevers, H., Klumperman, J., Levtchenko, E., Berkers, C.R., Verhaar, M.C., Altelaar, M., Masereeuw, R., Janssen, M.J. (2021) Cysteamine-bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis. EMBO Molecular Medicine. 13(7):e13067.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping