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Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis

Amer Jamalpoor, Charlotte AGH van Gelder, Fjodor A Yousef Yengej, Esther A Zaal, Sante Princiero Berlingerio, Koenraad R Veys, Carla Pou Casellas, Koen Voskuil, Khaled Essa, Carola ME Ammerlaan, Laura Rita Rega, Reini 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, View ORCID ProfileManoe J Janssen
doi: https://doi.org/10.1101/2020.02.10.941799
Amer Jamalpoor
1Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, The Netherlands
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Charlotte AGH van Gelder
2Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
3Netherlands Proteomics Center, Utrecht, The Netherlands
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Fjodor A Yousef Yengej
4Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands
5Department of Nephrology and Hypertension, University Medical Centre Utrecht, Utrecht, the Netherlands
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Esther A Zaal
2Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
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Sante Princiero Berlingerio
6Department of Pediatric Nephrology & Growth and Regeneration, University Hospitals Leuven & KU Leuven, Leuven, Belgium
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Koenraad R Veys
6Department of Pediatric Nephrology & Growth and Regeneration, University Hospitals Leuven & KU Leuven, Leuven, Belgium
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Carla Pou Casellas
1Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, The Netherlands
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Koen Voskuil
1Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, The Netherlands
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Khaled Essa
1Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, The Netherlands
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Carola ME Ammerlaan
4Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands
5Department of Nephrology and Hypertension, University Medical Centre Utrecht, Utrecht, the Netherlands
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Laura Rita Rega
7Renal Diseases Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
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Reini van der Welle
8Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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Marc R Lilien
9Department of Pediatric Nephrology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, the Netherlands
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Maarten B Rookmaaker
5Department of Nephrology and Hypertension, University Medical Centre Utrecht, Utrecht, the Netherlands
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Hans Clevers
4Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands
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Judith Klumperman
8Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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Elena Levtchenko
6Department of Pediatric Nephrology & Growth and Regeneration, University Hospitals Leuven & KU Leuven, Leuven, Belgium
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Celia R Berkers
2Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
10Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
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Marianne C Verhaar
5Department of Nephrology and Hypertension, University Medical Centre Utrecht, Utrecht, the Netherlands
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Maarten Altelaar
2Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
3Netherlands Proteomics Center, Utrecht, The Netherlands
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Rosalinde Masereeuw
1Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, The Netherlands
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Manoe J Janssen
1Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, The Netherlands
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  • ORCID record for Manoe J Janssen
  • For correspondence: m.j.janssen@uu.nl
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Abstract

Nephropathic cystinosis is a severe monogenetic 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 proximal tubulopathy. Here, we developed a new therapeutic strategy by applying an omics-based strategy to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis. We identified alpha-ketoglutarate as a key metabolite linking cystinosin loss, lysosomal autophagy defect and proximal tubular impairment in cystinosis. This insight offered a bicalutamide-cysteamine combination treatment as a novel dual target pharmacological approach for the phenotypical correction of cystinotic proximal tubule cells, patient-derived kidney tubuloids and cystinotic zebrafish.

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Posted February 11, 2020.
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Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis
Amer Jamalpoor, Charlotte AGH van Gelder, Fjodor A Yousef Yengej, Esther A Zaal, Sante Princiero Berlingerio, Koenraad R Veys, Carla Pou Casellas, Koen Voskuil, Khaled Essa, Carola ME Ammerlaan, Laura Rita Rega, Reini 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
bioRxiv 2020.02.10.941799; doi: https://doi.org/10.1101/2020.02.10.941799
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Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis
Amer Jamalpoor, Charlotte AGH van Gelder, Fjodor A Yousef Yengej, Esther A Zaal, Sante Princiero Berlingerio, Koenraad R Veys, Carla Pou Casellas, Koen Voskuil, Khaled Essa, Carola ME Ammerlaan, Laura Rita Rega, Reini 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
bioRxiv 2020.02.10.941799; doi: https://doi.org/10.1101/2020.02.10.941799

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