Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency

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.

Automated summary

Multiple sulfatase deficiency (MSD) is caused by pathogenic variants in the SUMF1 gene, leading to dysfunction of the formylglycine-generating enzyme (FGE). Therapeutic options for MSD are limited, but treatment with retinoids tazarotene and bexarotene showed promising results in restoring sulfatase activities and normalizing lysosomal position and size. In addition, these retinoids increased stability of FGE variants, suggesting a potential therapeutic option for MSD patients using these drugs.