Schlotawa, Lars, Tyka, Karolina, Kettwig, Matthias, C Ahrens-Nicklas, Rebecca, Baud, Matthias G.J., Berulava, Tea, Brunetti-Pierri, Nicola, Gagne, Alyssa, M Herbst, Zackary, A Maguire, Jean, Monfregola, Jlenia, Pena, Tonatiuh, Radhakrishnan, Karthikeyan, Schröder, Sophie, A Waxman, Elisa, Ballabio, Andrea, Dierks, Thomas, Fischer, André, L French, Deborah, Gelb, Michael H. and Gärtner, Jutta (2023) Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency. EMBO Molecular Medicine, 15 (3), [e14837]. (doi:10.15252/emmm.202114837).
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.
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