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000255144 1001_ $$00000-0002-7415-4905$$aSchlotawa, Lars$$b0
000255144 245__ $$aDrug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency.
000255144 260__ $$aHeidelberg$$bEMBO Press$$c2023
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000255144 520__ $$aMultiple 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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000255144 650_7 $$0A61RXM4375$$2NLM Chemicals$$aBexarotene
000255144 650_7 $$2Other$$adrug screening
000255144 650_7 $$2Other$$aformylglycine-generating enzyme
000255144 650_7 $$2Other$$alysosomal disorder
000255144 650_7 $$2Other$$aretinoids
000255144 650_7 $$2Other$$asulfatase-modifying factor 1
000255144 650_7 $$081BDR9Y8PS$$2NLM Chemicals$$atazarotene
000255144 650_7 $$0EC 3.1.6.-$$2NLM Chemicals$$aSulfatases
000255144 650_7 $$0EC 3.1.6.-$$2NLM Chemicals$$aSUMF1 protein, human
000255144 650_7 $$0EC 1.8.-$$2NLM Chemicals$$aOxidoreductases Acting on Sulfur Group Donors
000255144 650_2 $$2MeSH$$aHumans
000255144 650_2 $$2MeSH$$aMultiple Sulfatase Deficiency Disease: diagnosis
000255144 650_2 $$2MeSH$$aMultiple Sulfatase Deficiency Disease: genetics
000255144 650_2 $$2MeSH$$aMultiple Sulfatase Deficiency Disease: pathology
000255144 650_2 $$2MeSH$$aBexarotene
000255144 650_2 $$2MeSH$$aDrug Evaluation, Preclinical
000255144 650_2 $$2MeSH$$aSulfatases: genetics
000255144 650_2 $$2MeSH$$aOxidoreductases Acting on Sulfur Group Donors
000255144 7001_ $$00000-0002-4169-1675$$aTyka, Karolina$$b1
000255144 7001_ $$00000-0003-4804-7716$$aKettwig, Matthias$$b2
000255144 7001_ $$aAhrens-Nicklas, Rebecca C$$b3
000255144 7001_ $$00000-0003-3714-4350$$aBaud, Matthias$$b4
000255144 7001_ $$0P:(DE-2719)2811247$$aBerulava, Tea$$b5$$udzne
000255144 7001_ $$00000-0002-6895-8819$$aBrunetti-Pierri, Nicola$$b6
000255144 7001_ $$00000-0002-5636-4618$$aGagne, Alyssa$$b7
000255144 7001_ $$aHerbst, Zackary M$$b8
000255144 7001_ $$aMaguire, Jean A$$b9
000255144 7001_ $$aMonfregola, Jlenia$$b10
000255144 7001_ $$0P:(DE-2719)2811063$$aPena Centeno, Tonatiuh$$b11$$udzne
000255144 7001_ $$00000-0003-1731-7410$$aRadhakrishnan, Karthikeyan$$b12
000255144 7001_ $$0P:(DE-2719)9001406$$aSchroeder, Sophie$$b13$$udzne
000255144 7001_ $$00000-0003-4562-7969$$aWaxman, Elisa A$$b14
000255144 7001_ $$00000-0003-1381-4604$$aBallabio, Andrea$$b15
000255144 7001_ $$aDierks, Thomas$$b16
000255144 7001_ $$0P:(DE-2719)2000047$$aFischer, Andre$$b17$$udzne
000255144 7001_ $$aFrench, Deborah L$$b18
000255144 7001_ $$aGelb, Michael H$$b19
000255144 7001_ $$0P:(DE-2719)2811933$$aGärtner, Jutta$$b20$$udzne
000255144 773__ $$0PERI:(DE-600)2485479-7$$a10.15252/emmm.202114837$$n3$$pe14837$$tEMBO molecular medicine$$v15$$x1757-4676$$y2023
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