255144 20240302115207.0 pmc:PMC9994482 pmc 10.15252/emmm.202114837 doi pmid:36789546 pmid 1757-4676 ISSN 1715-4684 ISSN 1757-4684 ISSN altmetric:142565747 altmetric DZNE-2023-00263 English 610 Schlotawa, Lars 0000-0002-7415-4905 0 Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency. Heidelberg 2023 EMBO Press article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1709307423_5355 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote CC BY 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. 352 - Disease Mechanisms (POF4-352) G:(DE-HGF)POF4-352 POF4-352 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de Bexarotene A61RXM4375 NLM Chemicals drug screening Other formylglycine-generating enzyme Other lysosomal disorder Other retinoids Other sulfatase-modifying factor 1 Other tazarotene 81BDR9Y8PS NLM Chemicals Sulfatases EC 3.1.6.- NLM Chemicals SUMF1 protein, human EC 3.1.6.- NLM Chemicals Oxidoreductases Acting on Sulfur Group Donors EC 1.8.- NLM Chemicals Humans MeSH Multiple Sulfatase Deficiency Disease: diagnosis MeSH Multiple Sulfatase Deficiency Disease: genetics MeSH Multiple Sulfatase Deficiency Disease: pathology MeSH Bexarotene MeSH Drug Evaluation, Preclinical MeSH Sulfatases: genetics MeSH Oxidoreductases Acting on Sulfur Group Donors MeSH Tyka, Karolina 0000-0002-4169-1675 1 Kettwig, Matthias 0000-0003-4804-7716 2 Ahrens-Nicklas, Rebecca C 3 Baud, Matthias 0000-0003-3714-4350 4 Berulava, Tea P:(DE-2719)2811247 5 dzne Brunetti-Pierri, Nicola 0000-0002-6895-8819 6 Gagne, Alyssa 0000-0002-5636-4618 7 Herbst, Zackary M 8 Maguire, Jean A 9 Monfregola, Jlenia 10 Pena Centeno, Tonatiuh P:(DE-2719)2811063 11 dzne Radhakrishnan, Karthikeyan 0000-0003-1731-7410 12 Schroeder, Sophie P:(DE-2719)9001406 13 dzne Waxman, Elisa A 0000-0003-4562-7969 14 Ballabio, Andrea 0000-0003-1381-4604 15 Dierks, Thomas 16 Fischer, Andre P:(DE-2719)2000047 17 dzne French, Deborah L 18 Gelb, Michael H 19 Gärtner, Jutta P:(DE-2719)2811933 20 dzne 10.15252/emmm.202114837 PERI:(DE-600)2485479-7 3 e14837 EMBO molecular medicine 15 2023 1757-4676 http://pub.dzne.de/record/255144/files/DZNE-2023-00263.pdf OpenAccess http://pub.dzne.de/record/255144/files/DZNE-2023-00263.pdf?subformat=pdfa pdfa OpenAccess oai:pub.dzne.de:255144 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 5 P:(DE-2719)2811247 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 11 P:(DE-2719)2811063 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 13 P:(DE-2719)9001406 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 17 P:(DE-2719)2000047 External Institute I:(DE-HGF)0 Extern 20 P:(DE-2719)2811933 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-352 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Disease Mechanisms 0 2023 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2023-10-25 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2023-10-25 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2023-10-25 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2022-11-29 Creative Commons Attribution CC BY 4.0 LIC:(DE-HGF)CCBY4 HGFVOC JCR StatID:(DE-HGF)0100 StatID EMBO MOL MED : 2022 2023-10-25 IF >= 10 StatID:(DE-HGF)9910 StatID EMBO MOL MED : 2022 2023-10-25 DBCoverage StatID:(DE-HGF)0501 StatID DOAJ Seal 2021-07-19T13:19:31Z WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2022-11-29 DBCoverage StatID:(DE-HGF)0500 StatID DOAJ 2021-07-19T13:19:31Z DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2023-10-25 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2023-10-25 OpenAccess StatID:(DE-HGF)0510 StatID Peer Review StatID:(DE-HGF)0030 StatID DOAJ : Anonymous peer review, Double anonymous peer review 2021-07-19T13:19:31Z Article Processing Charges StatID:(DE-HGF)0561 StatID 2022-11-29 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2022-11-29 DBCoverage StatID:(DE-HGF)0320 StatID PubMed Central 2023-10-25 Fees StatID:(DE-HGF)0700 StatID 2022-11-29 I:(DE-2719)1410002 AG Fischer Epigenetics and Systems Medicine in Neurodegenerative Diseases 0 I:(DE-2719)1440016 Bioinformatics and Genome Dynamics Core Bioinformatics and Genome Dynamics Core 1 journal VDB I:(DE-2719)1410002 I:(DE-2719)1440016 UNRESTRICTED FullTexts