Home > Publications Database > Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency. > print

001     255144
005     20240302115207.0
024 7 _ |a pmc:PMC9994482
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024 7 _ |a 10.15252/emmm.202114837
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024 7 _ |a pmid:36789546
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024 7 _ |a 1757-4676
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024 7 _ |a 1715-4684
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024 7 _ |a 1757-4684
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037 _ _ |a DZNE-2023-00263
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Schlotawa, Lars
|0 0000-0002-7415-4905
|b 0
245 _ _ |a Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency.
260 _ _ |a Heidelberg
|c 2023
|b EMBO Press
336 7 _ |a article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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500 _ _ |a CC BY
520 _ _ |a 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.
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650 _ 7 |a Bexarotene
|0 A61RXM4375
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650 _ 7 |a drug screening
|2 Other
650 _ 7 |a formylglycine-generating enzyme
|2 Other
650 _ 7 |a lysosomal disorder
|2 Other
650 _ 7 |a retinoids
|2 Other
650 _ 7 |a sulfatase-modifying factor 1
|2 Other
650 _ 7 |a tazarotene
|0 81BDR9Y8PS
|2 NLM Chemicals
650 _ 7 |a Sulfatases
|0 EC 3.1.6.-
|2 NLM Chemicals
650 _ 7 |a SUMF1 protein, human
|0 EC 3.1.6.-
|2 NLM Chemicals
650 _ 7 |a Oxidoreductases Acting on Sulfur Group Donors
|0 EC 1.8.-
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Multiple Sulfatase Deficiency Disease: diagnosis
|2 MeSH
650 _ 2 |a Multiple Sulfatase Deficiency Disease: genetics
|2 MeSH
650 _ 2 |a Multiple Sulfatase Deficiency Disease: pathology
|2 MeSH
650 _ 2 |a Bexarotene
|2 MeSH
650 _ 2 |a Drug Evaluation, Preclinical
|2 MeSH
650 _ 2 |a Sulfatases: genetics
|2 MeSH
650 _ 2 |a Oxidoreductases Acting on Sulfur Group Donors
|2 MeSH
700 1 _ |a Tyka, Karolina
|0 0000-0002-4169-1675
|b 1
700 1 _ |a Kettwig, Matthias
|0 0000-0003-4804-7716
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700 1 _ |a Ahrens-Nicklas, Rebecca C
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700 1 _ |a Baud, Matthias
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700 1 _ |a Berulava, Tea
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700 1 _ |a Brunetti-Pierri, Nicola
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700 1 _ |a Gagne, Alyssa
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700 1 _ |a Herbst, Zackary M
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700 1 _ |a Maguire, Jean A
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700 1 _ |a Monfregola, Jlenia
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700 1 _ |a Pena Centeno, Tonatiuh
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700 1 _ |a Radhakrishnan, Karthikeyan
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700 1 _ |a Schroeder, Sophie
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700 1 _ |a Waxman, Elisa A
|0 0000-0003-4562-7969
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700 1 _ |a Ballabio, Andrea
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700 1 _ |a Dierks, Thomas
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700 1 _ |a Fischer, Andre
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700 1 _ |a French, Deborah L
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700 1 _ |a Gelb, Michael H
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700 1 _ |a Gärtner, Jutta
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