17 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 Centeno, Tonatiuh Radhakrishnan, Karthikeyan Schroeder, Sophie Waxman, Elisa A Ballabio, Andrea Dierks, Thomas Fischer, Andre French, Deborah L Gelb, Michael H Gärtner, Jutta AG Fischer Bioinformatics and Genome Dynamics Core EMBO molecular medicine EMBO molecular medicine EMBO Press Heidelberg 1757-4676 10.15252/emmm.202114837 English e14837 3 15 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. CC BY ; PUB:(DE-HGF)16, ; 0, ; Humans Multiple Sulfatase Deficiency Disease: diagnosis Multiple Sulfatase Deficiency Disease: genetics Multiple Sulfatase Deficiency Disease: pathology Bexarotene Drug Evaluation, Preclinical Sulfatases: genetics Oxidoreductases Acting on Sulfur Group Donors Bexarotene drug screening formylglycine-generating enzyme lysosomal disorder retinoids sulfatase-modifying factor 1 tazarotene Sulfatases SUMF1 protein, human Oxidoreductases Acting on Sulfur Group Donors Journal Article 2023 DZNE-2023-00263 2023 pmc:PMC9994482 pmid:36789546 https://pub.dzne.de/record/255144 https://doi.org/10.15252/emmm.202114837