Schlotawa l, Matysiak K, Kettwig M, Ahrens-Nicklas RC, Baud M, Berulava T, Brunetti-Pierri N, Gagne A, Herbst ZM, Maguire JA, Monfregola J, Pena T, Radhakrishnan K, Schröder S, Waxman EA, Ballabio A, Dierks T, Fischer A, French DL, Gelb MH, Gärtner J
Neuropediatrics 2023; 54(S 01): S1-S32.
Background/Purpose: Multiple sulfatase deficiency (MSD, MIM #272200) is an ultra-rare neurodegenerative lysosomal disorder. MSD is caused by mutations in the SUMF1 gene encoding the formylglycine-generating enzyme (FGE). FGE catalyzes the posttranslational activation of all newly synthesized cellular sulfatases. In MSD, FGE function is impaired resulting in reduced or even absent activities of cellular sulfatases. Patients with MSD present with a unique combination of clinical signs and symptoms that resemble lysosomal disorders caused by single sulfatase deficiencies because the majority of cellular sulfatases are localized in lysosomes. Among these are different mucopolysaccharidosis subtypes and metachromatic leukodystrophy. No curative therapy exists for MSD and treatment of patients is mostly palliative and restricted to alleviation of symptoms.
Methods: To address the high-unmet need for a therapy, we aimed for repurposing existing drugs for MSD. We developed a high-throughput screening assay and screened 785 FDA-approved drugs for their ability to rescue arylsulfatase A activity in MSD patient derived fibroblasts.
Results: Third-generation retinoids tazarotene and bexarotene revealed a dose- and time-dependent increase of sulfatase activities, improvement of relevant cellular markers of disease, including clearance of glycosaminoglycans, and normalization of lysosomal size and position upon treatment, independent of the pathogenic variant. Treatment of SUMF1-deficient induced pluripotent stem cells (iPSC)-derived neuronal progenitor cells (NPC) revealed a response across cell types. Both drugs work via retinoic acid receptor subtypes in MSD cells finally increasing FGE variant stability and functionality.
Conclusion: The results are a promising first step toward future research with the ultimate goal of repurposing tazarotene and bexarotene as a therapy for MSD patients.