Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency. Issue 3 (15th February 2023)

• Record Type: Journal Article
• Authors: Schlotawa, Lars; Tyka, Karolina; Kettwig, Matthias; Ahrens‐Nicklas, Rebecca C; Baud, Matthias; Berulava, Tea; Brunetti‐Pierri, Nicola; Gagne, Alyssa; Herbst, Zackary M; Maguire, Jean A; Monfregola, Jlenia; Pena, Tonatiuh; Radhakrishnan, Karthikeyan; Schröder, Sophie; Waxman, Elisa A; Ballabio, Andrea; Dierks, Thomas; Fischer, André; French, Deborah L; Gelb, Michael H; Gärtner, Jutta
• Is Part Of: EMBO molecular medicine. Volume 15:Issue 3(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-02-15
• Subjects: drug screening -- formylglycine‐generating enzyme -- lysosomal disorder -- retinoids -- sulfatase‐modifying factor 1; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202114837
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: The ultra‐rare lysosomal disease Multiple Sulfatase Deficiency (MSD) is a progressive currently incurable neurodegenerative disorder. Here we demonstrate that retinoids tazarotene and bexarotene, identified by a high‐throughput drug screening, are active therapeutic agents for MSD in‐vitro . Tazarotene and bexarotene treatment of different MSD patient derived cells restored defective sulfatases activities across different SUMF1 mutations and led to improved cellular disease pathology. Tazarotene and bexarotene act via RAR and RXR receptors in MSD cells and result in transcriptional response but do not regulate MSD target genes. Residual FGE functionality was required for the intracellular mode of action of tazarotene and bexarotene to increase sulfatase activities in MSD. The intracellular stability of degradation prone MSD causing FGE variants was increased by simultaneous tazarotene and bexarotene treatment and improved sulfatase activation. Abstract : The ultra‐rare lysosomal disease Multiple Sulfatase Deficiency (MSD) is a progressive currently incurable neurodegenerative disorder. Here we demonstrate that retinoids tazarotene and bexarotene, identified by a high‐throughput drug screening, are active therapeutic agents for MSD in‐vitro .