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Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9994482/ https://www.ncbi.nlm.nih.gov/pubmed/36789546 http://dx.doi.org/10.15252/emmm.202114837 |
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author | Schlotawa, Lars Tyka, Karolina Kettwig, Matthias Ahrens‐Nicklas, Rebecca C Baud, Matthias Berulava, Tea Brunetti‐Pierri, Nicola Gagne, Alyssa Herbst, Zackary M Maguire, Jean A Monfregola, Jlenia Pena, Tonatiuh Radhakrishnan, Karthikeyan Schröder, Sophie Waxman, Elisa A Ballabio, Andrea Dierks, Thomas Fischer, André French, Deborah L Gelb, Michael H Gärtner, Jutta |
author_facet | Schlotawa, Lars Tyka, Karolina Kettwig, Matthias Ahrens‐Nicklas, Rebecca C Baud, Matthias Berulava, Tea Brunetti‐Pierri, Nicola Gagne, Alyssa Herbst, Zackary M Maguire, Jean A Monfregola, Jlenia Pena, Tonatiuh Radhakrishnan, Karthikeyan Schröder, Sophie Waxman, Elisa A Ballabio, Andrea Dierks, Thomas Fischer, André French, Deborah L Gelb, Michael H Gärtner, Jutta |
author_sort | Schlotawa, Lars |
collection | PubMed |
description | 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 | Online Article Text |
id | pubmed-9994482 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-99944822023-03-09 Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency Schlotawa, Lars Tyka, Karolina Kettwig, Matthias Ahrens‐Nicklas, Rebecca C Baud, Matthias Berulava, Tea Brunetti‐Pierri, Nicola Gagne, Alyssa Herbst, Zackary M Maguire, Jean A Monfregola, Jlenia Pena, Tonatiuh Radhakrishnan, Karthikeyan Schröder, Sophie Waxman, Elisa A Ballabio, Andrea Dierks, Thomas Fischer, André French, Deborah L Gelb, Michael H Gärtner, Jutta EMBO Mol Med Articles 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. John Wiley and Sons Inc. 2023-02-15 /pmc/articles/PMC9994482/ /pubmed/36789546 http://dx.doi.org/10.15252/emmm.202114837 Text en © 2023 The Authors. Published under the terms of the CC BY 4.0 license. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Schlotawa, Lars Tyka, Karolina Kettwig, Matthias Ahrens‐Nicklas, Rebecca C Baud, Matthias Berulava, Tea Brunetti‐Pierri, Nicola Gagne, Alyssa Herbst, Zackary M Maguire, Jean A Monfregola, Jlenia Pena, Tonatiuh Radhakrishnan, Karthikeyan Schröder, Sophie Waxman, Elisa A Ballabio, Andrea Dierks, Thomas Fischer, André French, Deborah L Gelb, Michael H Gärtner, Jutta Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency |
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 | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9994482/ https://www.ncbi.nlm.nih.gov/pubmed/36789546 http://dx.doi.org/10.15252/emmm.202114837 |
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