engSchlotawa, LarsTyka, KarolinaMonfregola, JleniaPena Centeno, TonatiuhRadhakrishnan, KarthikeyanSchroeder, SophieWaxman, Elisa ABallabio, AndreaDierks, ThomasFischer, AndreFrench, Deborah LGelb, Michael HKettwig, MatthiasGärtner, JuttaAhrens-Nicklas, Rebecca CBaud, MatthiasBerulava, TeaBrunetti-Pierri, NicolaGagne, AlyssaHerbst, Zackary MMaguire, Jean ADrug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency.info:eu-repo/classification/ddc/610HumansMultiple Sulfatase Deficiency Disease: diagnosisMultiple Sulfatase Deficiency Disease: geneticsMultiple Sulfatase Deficiency Disease: pathologyBexaroteneDrug Evaluation, PreclinicalSulfatases: geneticsOxidoreductases Acting on Sulfur Group DonorsBexarotenedrug screeningformylglycine-generating enzymelysosomal disorderretinoidssulfatase-modifying factor 1tazaroteneSulfatasesSUMF1 protein, humanOxidoreductases Acting on Sulfur Group DonorsMultiple 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.EMBO molecular medicine 15(3), e14837 (2023). doi:10.15252/emmm.202114837info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionEMBO Press2023info:eu-repo/semantics/openAccessDEhttps://pub.dzne.de/record/255144https://pub.dzne.de/search?p=id:%22DZNE-2023-00263%22Researchersinfo:eu-repo/semantics/altIdentifier/issn/1757-4676info:eu-repo/semantics/altIdentifier/issn/1715-4684info:eu-repo/semantics/altIdentifier/pmid/pmid:36789546info:eu-repo/semantics/altIdentifier/issn/1757-4684info:eu-repo/semantics/altIdentifier/doi/10.15252/emmm.202114837