Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency
Abstract Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine‐generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent...
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Springer Nature
2023-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202114837 |
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| author | Lars Schlotawa Karolina Tyka Matthias Kettwig Rebecca C Ahrens‐Nicklas Matthias Baud Tea Berulava Nicola Brunetti‐Pierri Alyssa Gagne Zackary M Herbst Jean A Maguire Jlenia Monfregola Tonatiuh Pena Karthikeyan Radhakrishnan Sophie Schröder Elisa A Waxman Andrea Ballabio Thomas Dierks André Fischer Deborah L French Michael H Gelb Jutta Gärtner |
| author_facet | Lars Schlotawa Karolina Tyka Matthias Kettwig Rebecca C Ahrens‐Nicklas Matthias Baud Tea Berulava Nicola Brunetti‐Pierri Alyssa Gagne Zackary M Herbst Jean A Maguire Jlenia Monfregola Tonatiuh Pena Karthikeyan Radhakrishnan Sophie Schröder Elisa A Waxman Andrea Ballabio Thomas Dierks André Fischer Deborah L French Michael H Gelb Jutta Gärtner |
| author_sort | Lars Schlotawa |
| collection | DOAJ |
| description | Abstract Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine‐generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent sulfatase activities and, as a result, clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are limited and mostly palliative. We performed a screen of FDA‐approved drugs using immortalized MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of primary MSD fibroblasts with tazarotene and bexarotene, two retinoids, led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose‐ and time‐dependent manner, reduced glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients. |
| format | Article |
| id | doaj-art-b678e69f8129428e87e0aebc0aa61cd4 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-b678e69f8129428e87e0aebc0aa61cd42025-08-24T11:43:22ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-02-0115312110.15252/emmm.202114837Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiencyLars Schlotawa0Karolina Tyka1Matthias Kettwig2Rebecca C Ahrens‐Nicklas3Matthias Baud4Tea Berulava5Nicola Brunetti‐Pierri6Alyssa Gagne7Zackary M Herbst8Jean A Maguire9Jlenia Monfregola10Tonatiuh Pena11Karthikeyan Radhakrishnan12Sophie Schröder13Elisa A Waxman14Andrea Ballabio15Thomas Dierks16André Fischer17Deborah L French18Michael H Gelb19Jutta Gärtner20Department of Paediatrics and Adolescent Medicine, University Medical Centre GöttingenDepartment of Paediatrics and Adolescent Medicine, University Medical Centre GöttingenDepartment of Paediatrics and Adolescent Medicine, University Medical Centre GöttingenDivision of Human Genetics and Metabolism, The Children's Hospital of PhiladelphiaSchool of Chemistry and Institute for Life Sciences, University of SouthamptonDepartment for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Centre for Neurodegenerative DiseasesTelethon Institute of Genetics and MedicineCenter for Cellular and Molecular Therapeutics, The Children's Hospital of PhiladelphiaDepartment of Chemistry, University of WashingtonCenter for Cellular and Molecular Therapeutics, The Children's Hospital of PhiladelphiaTelethon Institute of Genetics and MedicineDepartment for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Centre for Neurodegenerative DiseasesFaculty of Chemistry, Biochemistry I, Bielefeld UniversityDepartment for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Centre for Neurodegenerative DiseasesCenter for Cellular and Molecular Therapeutics, The Children's Hospital of PhiladelphiaTelethon Institute of Genetics and MedicineFaculty of Chemistry, Biochemistry I, Bielefeld UniversityDepartment for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Centre for Neurodegenerative DiseasesCenter for Cellular and Molecular Therapeutics, The Children's Hospital of PhiladelphiaDepartment of Chemistry, University of WashingtonDepartment of Paediatrics and Adolescent Medicine, University Medical Centre GöttingenAbstract Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine‐generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent sulfatase activities and, as a result, clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are limited and mostly palliative. We performed a screen of FDA‐approved drugs using immortalized MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of primary MSD fibroblasts with tazarotene and bexarotene, two retinoids, led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose‐ and time‐dependent manner, reduced glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients. https://doi.org/10.15252/emmm.202114837drug screeningformylglycine‐generating enzymelysosomal disorderretinoidssulfatase‐modifying factor 1 |
| spellingShingle | Lars Schlotawa Karolina Tyka Matthias Kettwig Rebecca C Ahrens‐Nicklas Matthias Baud Tea Berulava Nicola Brunetti‐Pierri Alyssa Gagne Zackary M Herbst Jean A Maguire Jlenia Monfregola Tonatiuh Pena Karthikeyan Radhakrishnan Sophie Schröder Elisa A Waxman Andrea Ballabio Thomas Dierks André Fischer Deborah L French Michael H Gelb Jutta Gärtner Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency EMBO Molecular Medicine drug screening formylglycine‐generating enzyme lysosomal disorder retinoids sulfatase‐modifying factor 1 |
| title | Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency |
| title_full | Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency |
| title_fullStr | Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency |
| title_full_unstemmed | Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency |
| title_short | Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency |
| title_sort | drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency |
| topic | drug screening formylglycine‐generating enzyme lysosomal disorder retinoids sulfatase‐modifying factor 1 |
| url | https://doi.org/10.15252/emmm.202114837 |
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