Cysteamine-bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis

Amer Jamalpoor; Charlotte Agh van Gelder; Fjodor A Yousef Yengej; Esther A Zaal; Sante P Berlingerio; Koenraad R Veys; Carla Pou Casellas; Koen Voskuil; Khaled Essa; Carola Me Ammerlaan; Laura Rita Rega; Reini En van der Welle; Marc R Lilien; Maarten B Rookmaaker; Hans Clevers; Judith Klumperman; Elena Levtchenko; Celia R Berkers; Marianne C Verhaar; Maarten Altelaar; Rosalinde Masereeuw; Manoe J Janssen

doi:10.15252/emmm.202013067

Cysteamine-bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis

Amer Jamalpoor, Charlotte Agh van Gelder, Fjodor A Yousef Yengej, Esther A Zaal, Sante P Berlingerio, Koenraad R Veys, Carla Pou Casellas, Koen Voskuil, Khaled Essa, Carola Me Ammerlaan, Laura Rita Rega, Reini En 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

Research output: Contribution to journal › Article › Academic › peer-review

3 Downloads (Pure)

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.

Original language	English
Article number	e13067
Pages (from-to)	1-20
Journal	Embo Molecular Medicine
Volume	13
Issue number	7
Early online date	24 Jun 2021
DOIs	https://doi.org/10.15252/emmm.202013067
Publication status	Published - 7 Jul 2021

Keywords

alpha-ketoglutarate
Bicalutamide combination therapy
cysteamine
cystinosis
renal Fanconi syndrome

Access to Document

10.15252/emmm.202013067Licence: CC BY

EMBO Mol Med - 2021 - Jamalpoor - Cysteamine bicalutamide combination therapy corrects proximal tubule phenotype inFinal published version, 3.02 MBLicence: CC BY

Cite this

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., ... Janssen, M. J. (2021). Cysteamine-bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis. Embo Molecular Medicine, 13(7), 1-20. Article e13067. https://doi.org/10.15252/emmm.202013067

@article{377e15838f854e39a66dc172aede6859,

title = "Cysteamine-bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis",

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.",

keywords = "alpha-ketoglutarate, Bicalutamide combination therapy, cysteamine, cystinosis, renal Fanconi syndrome",

author = "Amer Jamalpoor and {van Gelder}, {Charlotte Agh} and {Yousef Yengej}, {Fjodor A} and Zaal, {Esther A} and Berlingerio, {Sante P} and Veys, {Koenraad R} and {Pou Casellas}, Carla and Koen Voskuil and Khaled Essa and Ammerlaan, {Carola Me} and Rega, {Laura Rita} and {van der Welle}, {Reini En} and Lilien, {Marc R} and Rookmaaker, {Maarten B} and Hans Clevers and Judith Klumperman and Elena Levtchenko and Berkers, {Celia R} and Verhaar, {Marianne C} and Maarten Altelaar and Rosalinde Masereeuw and Janssen, {Manoe J}",

note = "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: {\textcopyright} 2021 The Authors. Published under the terms of the CC BY 4.0 license",

year = "2021",

month = jul,

day = "7",

doi = "10.15252/emmm.202013067",

language = "English",

volume = "13",

pages = "1--20",

journal = "Embo Molecular Medicine",

issn = "1757-4676",

publisher = "Wiley-Blackwell",

number = "7",

}

Jamalpoor, A, van Gelder, CA, Yousef Yengej, FA, Zaal, EA, Berlingerio, SP, Veys, KR, Pou Casellas, C, Voskuil, K, Essa, K, Ammerlaan, CM, Rega, LR, van der Welle, RE, Lilien, MR, Rookmaaker, MB, Clevers, H, Klumperman, J, Levtchenko, E, Berkers, CR, Verhaar, MC, Altelaar, M, Masereeuw, R & Janssen, MJ 2021, 'Cysteamine-bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis', Embo Molecular Medicine, vol. 13, no. 7, e13067, pp. 1-20. https://doi.org/10.15252/emmm.202013067

TY - JOUR

T1 - Cysteamine-bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis

AU - Jamalpoor, Amer

AU - van Gelder, Charlotte Agh

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 Me

AU - Rega, Laura Rita

AU - van der Welle, Reini En

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 - 10.15252/emmm.202013067

DO - 10.15252/emmm.202013067

M3 - Article

C2 - 34165243

SN - 1757-4676

VL - 13

SP - 1

EP - 20

JO - Embo Molecular Medicine

JF - Embo Molecular Medicine

IS - 7

M1 - e13067

ER -

Cysteamine-bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this