%0 Journal Article
%A Schlotawa, Lars
%A Tyka, Karolina
%A Kettwig, Matthias
%A Ahrens-Nicklas, Rebecca C
%A Baud, Matthias
%A Berulava, Tea
%A Brunetti-Pierri, Nicola
%A Gagne, Alyssa
%A Herbst, Zackary M
%A Maguire, Jean A
%A Monfregola, Jlenia
%A Pena Centeno, Tonatiuh
%A Radhakrishnan, Karthikeyan
%A Schroeder, Sophie
%A Waxman, Elisa A
%A Ballabio, Andrea
%A Dierks, Thomas
%A Fischer, Andre
%A French, Deborah L
%A Gelb, Michael H
%A Gärtner, Jutta
%T Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency.
%J EMBO molecular medicine
%V 15
%N 3
%@ 1757-4676
%C Heidelberg
%I EMBO Press
%M DZNE-2023-00263
%P e14837
%D 2023
%Z CC BY
%X 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.
%K Humans
%K Multiple Sulfatase Deficiency Disease: diagnosis
%K Multiple Sulfatase Deficiency Disease: genetics
%K Multiple Sulfatase Deficiency Disease: pathology
%K Bexarotene
%K Drug Evaluation, Preclinical
%K Sulfatases: genetics
%K Oxidoreductases Acting on Sulfur Group Donors
%K Bexarotene (NLM Chemicals)
%K drug screening (Other)
%K formylglycine-generating enzyme (Other)
%K lysosomal disorder (Other)
%K retinoids (Other)
%K sulfatase-modifying factor 1 (Other)
%K tazarotene (NLM Chemicals)
%K Sulfatases (NLM Chemicals)
%K SUMF1 protein, human (NLM Chemicals)
%K Oxidoreductases Acting on Sulfur Group Donors (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%2 pmc:PMC9994482
%$ pmid:36789546
%R 10.15252/emmm.202114837
%U https://pub.dzne.de/record/255144