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 Altelaar; Rosalinde Masereeuw; Manoe J. Janssen

doi:10.15252/emmm.202013067

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 journal › Article › Academic › peer-review

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
Number of pages	20
Journal	EMBO Molecular Medicine
Volume	13
Issue number	7
DOIs	https://doi.org/10.15252/emmm.202013067
Publication status	Published - 7 Jul 2021

Bibliographical 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:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license

Funding

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).

Keywords

alpha-ketoglutarate
Bicalutamide combination therapy
cysteamine
cystinosis
renal Fanconi syndrome

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emmm.202013067Final published version, 3.02 MBLicence: CC BY

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Jamalpoor, A., van Gelder, C. A. G. H., Yousef Yengej, F. A., Zaal, E. A., Berlingerio, S. P., Veys, K. R., Pou Casellas, C., Voskuil, K., Essa, K., Ammerlaan, C. M. E., Rega, L. R., van der Welle, R. E. N., 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

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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 A.G.H.} 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 M.E.} and Rega, {Laura Rita} and {van der Welle}, {Reini E.N.} 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",

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Jamalpoor, A, van Gelder, CAGH, Yousef Yengej, FA, Zaal, EA, Berlingerio, SP, Veys, KR, Pou Casellas, C, Voskuil, K, Essa, K, Ammerlaan, CME, Rega, LR, van der Welle, REN, 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 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 - 10.15252/emmm.202013067

DO - 10.15252/emmm.202013067

M3 - Article

AN - SCOPUS:85108368690

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

Bibliographical note

Funding

Keywords

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