In-vitro-Untersuchungen zur Wirkung von Apigenin als Therapeutikum für die Multiple Sulfatase Defizienz

In Vitro Studies on the Effect of Apigenin as a Therapeutic Agent for Multiple Sulfatase Deficiency

by Lilly Hutzschenreuter
Doctoral thesis
Date of Examination:2026-01-12
Date of issue:2025-12-02
Advisor:Prof. Dr. Lars Schlotawa
Referee:Prof. Dr. Lars Schlotawa
Referee:Prof. Dr. Silke J. Pauli
Persistent Address: http://dx.doi.org/10.53846/goediss-11663

 

 

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Abstract

English

Multiple Sulfatase Deficiency (MSD) is a rare, autosomal recessive lysosomal storage disorder caused by pathogenic variants in SUMF1, resulting in deficient activity of all cellular sulfatases. The lack of functional formylglycine-generating enzyme (FGE) prevents the post-translational activation of sulfatases and leads to progressive multisystemic disease manifestations. As no causal therapy is currently available, the identification of pharmacological approaches capable of stabilizing FGE or enhancing residual sulfatase activity is of high clinical interest. Previous high-throughput screening in MSD patient fibroblasts identified Apigenin, a naturally occurring flavonoid, as a potential candidate substance. This work investigates the therapeutic potential of Apigenin in vitro using immortalized MSD cells and fibroblasts from patients carrying different SUMF1 mutations. The study evaluates dose- and time-dependent effects of Apigenin on lysosomal and non-lysosomal sulfatase activities, its impact on FGE and arylsulfatase A (ARSA) expression, cellular viability, lysosomal characteristics, and storage of glycosaminoglycans (GAGs). Apigenin treatment resulted in a reproducible increase in the activities of several sulfatases, including ARSA, N-acetyl-galactosamine-6-sulfatase, and steroid sulfatase, accompanied by elevated ARSA protein expression. The increase in ARSA activity was observed across multiple patient-derived cell lines, suggesting mutation-independent efficacy. However, Apigenin also reduced cellular viability at higher concentrations and did not enhance FGE protein levels. Notably, treatment decreased GAG storage, although no improvement in lysosomal morphology was observed. Overall, Apigenin exhibits promising properties as a small-molecule modulator capable of enhancing residual sulfatase activity in MSD. Nevertheless, its cytotoxic effects and the incomplete understanding of its mechanism highlight the need for further mechanistic and in vivo studies. This work provides preliminary evidence supporting Apigenin as a candidate for future pharmacotherapeutic development in MSD.
Keywords: Multiple Sulfatase Deficiency; ARSA; FGE; lysosomal storage disorder; SUMF1; Apigenin