{"doi":"10.15252/emmm.202114837","title":"Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency","abstract":"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.","journal":"EMBO Molecular Medicine","year":2023,"id":356914,"datarank":0.6506380784409548,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.21708231475653003,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.21708231475653003,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":12,"citers_with_citation_signal":8,"citers_with_endowment":8,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9636,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE205555","GSE205556"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1106001,"name":"Karolina Tyka","orcid":"0000-0002-4169-1675","position":1,"is_corresponding":false},{"id":919764,"name":"Matthias Kettwig","orcid":"0000-0003-4804-7716","position":2,"is_corresponding":false},{"id":368519,"name":"Rebecca C. 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