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Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency

ABSTRACT: Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency

PROVIDER: PRJNA846323 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19552700_1.fastq.gz	Fastqsanger.gz
	SRR19552700_2.fastq.gz	Fastqsanger.gz
	SRR19552701_1.fastq.gz	Fastqsanger.gz
	SRR19552701_2.fastq.gz	Fastqsanger.gz
	SRR19552702_1.fastq.gz	Fastqsanger.gz

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Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency II

Project description:Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency II

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Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency II

Project description:We analysed differences in gene expression upon treatment of MSD patient fibroblast lines and control fibroblast lines with tazarotene and bexarotene or DMSO control (untreated condition)

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

Project description: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.

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Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency

Project description:We analysed differences in gene expression upon treatment of MSD patient fibroblast lines with either tazarotene or adapalene and DMSO control (untreated condition)

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Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency

Project description: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 sulfatase activities and clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are mostly palliative. We performed a screen of FDA-approved drugs using immortalised MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of MSD fibroblasts with tazarotene and bexarotene led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose- and time-dependent manner, 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.

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