Journal Article

DZNE-2023-00263

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency.

Schlotawa, L. ; Tyka, K. ; Kettwig, M. ; Ahrens-Nicklas, R. C. ; Baud, M. ; Berulava, T.DZNE* ; Brunetti-Pierri, N. ; Gagne, A. ; Herbst, Z. M. ; Maguire, J. A. ; Monfregola, J. ; Pena Centeno, T.DZNE* ; Radhakrishnan, K. ; Schroeder, S.DZNE* ; Waxman, E. A. ; Ballabio, A. ; Dierks, T. ; Fischer, A.DZNE* ; French, D. L. ; Gelb, M. H. ; Gärtner, J.Extern*

2023
EMBO Press Heidelberg

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Please use a persistent id in citations: 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.

Keyword(s): Humans (MeSH) ; Multiple Sulfatase Deficiency Disease: diagnosis (MeSH) ; Multiple Sulfatase Deficiency Disease: genetics (MeSH) ; Multiple Sulfatase Deficiency Disease: pathology (MeSH) ; Bexarotene (MeSH) ; Drug Evaluation, Preclinical (MeSH) ; Sulfatases: genetics (MeSH) ; Oxidoreductases Acting on Sulfur Group Donors (MeSH) ; Bexarotene ; drug screening ; formylglycine-generating enzyme ; lysosomal disorder ; retinoids ; sulfatase-modifying factor 1 ; tazarotene ; Sulfatases ; SUMF1 protein, human ; Oxidoreductases Acting on Sulfur Group Donors

Note: CC BY

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Contributing Institute(s):

1. Epigenetics and Systems Medicine in Neurodegenerative Diseases (AG Fischer)
2. Bioinformatics and Genome Dynamics Core (Bioinformatics and Genome Dynamics Core)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2023

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