TY - JOUR
T1 - Cysteamine–bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis
AU - Jamalpoor, Amer
AU - van Gelder, Charlotte A.G.H.
AU - Yousef Yengej, Fjodor A.
AU - Zaal, Esther A.
AU - Berlingerio, Sante P.
AU - Veys, Koenraad R.
AU - Pou Casellas, Carla
AU - Voskuil, Koen
AU - Essa, Khaled
AU - Ammerlaan, Carola M.E.
AU - Rega, Laura Rita
AU - van der Welle, Reini E.N.
AU - Lilien, Marc R.
AU - Rookmaaker, Maarten B.
AU - Clevers, Hans
AU - Klumperman, Judith
AU - Levtchenko, Elena
AU - Berkers, Celia R.
AU - Verhaar, Marianne C.
AU - Altelaar, Maarten
AU - Masereeuw, Rosalinde
AU - Janssen, Manoe J.
N1 - Funding Information: This work was financially supported by a grant from the Dutch Kidney Foundation (grant nr.150KG19) and the E‐Rare 2‐Joint Call 2014, Novel Therapies for Cystinosis grant from Zon‐MW (grant nr. 113301402). R.M., F.A.Y.Y., C.M.E.A., M.B.R. and M.C.V. gratefully acknowledge the support of the partners of “Regenerative Medicine Crossing Borders” (RegMed XB), Powered by Health~Holland, Top Sector Life Sciences & Health; and the Gravitation Program “Materials Driven Regeneration”, funded by the Netherlands Organization for Scientific Research (024.003.013). Funding Information: This work was financially supported by a grant from the Dutch Kidney Foundation (grant nr.150KG19) and the E-Rare 2-Joint Call 2014, Novel Therapies for Cystinosis grant from Zon-MW (grant nr. 113301402). R.M., F.A.Y.Y., C.M.E.A., M.B.R. and M.C.V. gratefully acknowledge the support of the partners of ?Regenerative Medicine Crossing Borders? (RegMed XB), Powered by Health~Holland, Top Sector Life Sciences & Health; and the Gravitation Program ?Materials Driven Regeneration?, funded by the Netherlands Organization for Scientific Research (024.003.013). Publisher Copyright: © 2021 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2021/7/7
Y1 - 2021/7/7
N2 - 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.
AB - 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.
KW - alpha-ketoglutarate
KW - Bicalutamide combination therapy
KW - cysteamine
KW - cystinosis
KW - renal Fanconi syndrome
UR - http://www.scopus.com/inward/record.url?scp=85108368690&partnerID=8YFLogxK
U2 - https://doi.org/10.15252/emmm.202013067
DO - https://doi.org/10.15252/emmm.202013067
M3 - Article
C2 - 34165243
SN - 1757-4676
VL - 13
JO - EMBO molecular medicine
JF - EMBO molecular medicine
IS - 7
M1 - e13067
ER -