TY  - JOUR
AU  - Schlotawa, Lars
AU  - Tyka, Karolina
AU  - Kettwig, Matthias
AU  - Ahrens-Nicklas, Rebecca C
AU  - Baud, Matthias
AU  - Berulava, Tea
AU  - Brunetti-Pierri, Nicola
AU  - Gagne, Alyssa
AU  - Herbst, Zackary M
AU  - Maguire, Jean A
AU  - Monfregola, Jlenia
AU  - Pena Centeno, Tonatiuh
AU  - Radhakrishnan, Karthikeyan
AU  - Schroeder, Sophie
AU  - Waxman, Elisa A
AU  - Ballabio, Andrea
AU  - Dierks, Thomas
AU  - Fischer, Andre
AU  - French, Deborah L
AU  - Gelb, Michael H
AU  - Gärtner, Jutta
TI  - Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency.
JO  - EMBO molecular medicine
VL  - 15
IS  - 3
SN  - 1757-4676
CY  - Heidelberg
PB  - EMBO Press
M1  - DZNE-2023-00263
SP  - e14837
PY  - 2023
N1  - CC BY
AB  - 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.
KW  - Humans
KW  - Multiple Sulfatase Deficiency Disease: diagnosis
KW  - Multiple Sulfatase Deficiency Disease: genetics
KW  - Multiple Sulfatase Deficiency Disease: pathology
KW  - Bexarotene
KW  - Drug Evaluation, Preclinical
KW  - Sulfatases: genetics
KW  - Oxidoreductases Acting on Sulfur Group Donors
KW  - Bexarotene (NLM Chemicals)
KW  - drug screening (Other)
KW  - formylglycine-generating enzyme (Other)
KW  - lysosomal disorder (Other)
KW  - retinoids (Other)
KW  - sulfatase-modifying factor 1 (Other)
KW  - tazarotene (NLM Chemicals)
KW  - Sulfatases (NLM Chemicals)
KW  - SUMF1 protein, human (NLM Chemicals)
KW  - Oxidoreductases Acting on Sulfur Group Donors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9994482
C6  - pmid:36789546
DO  - DOI:10.15252/emmm.202114837
UR  - https://pub.dzne.de/record/255144
ER  -