Journal Article

DZNE-2022-00405

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Assessment of FDA-Approved Drugs as a Therapeutic Approach for Niemann-Pick Disease Type C1 Using Patient-Specific iPSC-Based Model Systems.

Völkner, C. ; Pantoom, S. ; Liedtke, M. ; Lukas, J. ; Hermann, A.DZNE* ; Frech, M. J.

2022
MDPI Basel

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Please use a persistent id in citations: doi:10.3390/cells11030319

Abstract: Niemann-Pick type C1 (NP-C1) is a fatal, progressive neurodegenerative disease caused by mutations in the NPC1 gene. Mutations of NPC1 can result in a misfolded protein that is subsequently marked for proteasomal degradation. Such loss-of-function mutations lead to cholesterol accumulation in late endosomes and lysosomes. Pharmacological chaperones (PCs) are described to protect misfolded proteins from proteasomal degradation and are being discussed as a treatment strategy for NP-C1. Here, we used a combinatorial approach of high-throughput in silico screening of FDA-approved drugs and in vitro biochemical assays to identify potential PCs. The effects of the hit compounds identified by molecular docking were compared in vitro with 25-hydroxycholesterol (25-HC), which is known to act as a PC for NP-C1. We analyzed cholesterol accumulation, NPC1 protein content, and lysosomal localization in patient-specific fibroblasts, as well as in neural differentiated and hepatocyte-like cells derived from patient-specific induced pluripotent stem cells (iPSCs). One compound, namely abiraterone acetate, showed comparable results to 25-HC and restored NPC1 protein level, corrected the intracellular localization of NPC1, and consequently decreased cholesterol accumulation in NPC1-mutated fibroblasts and iPSC-derived neural differentiated and hepatocyte-like cells. The discovered PC altered not only the pathophysiological phenotype of cells carrying the I1061T mutation- known to be responsive to treatment with PCs-but an effect was also observed in cells carrying other NPC1 missense mutations. Therefore, we hypothesize that the PCs studied here may serve as an effective treatment strategy for a large group of NP-C1 patients.

Keyword(s): Cholesterol: metabolism (MeSH) ; Humans (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Molecular Docking Simulation (MeSH) ; Neurodegenerative Diseases: metabolism (MeSH) ; Niemann-Pick C1 Protein: genetics (MeSH) ; Niemann-Pick C1 Protein: metabolism (MeSH) ; Niemann-Pick Disease, Type C: drug therapy (MeSH) ; Niemann-Pick Disease, Type C: metabolism (MeSH) ; NPC1 ; in silico screening ; induced pluripotent stem cells ; molecular docking ; pharmacological chaperones ; Niemann-Pick C1 Protein ; Cholesterol

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Contributing Institute(s):

1. AG Hermann Rostock / Greifswald (AG Hermann2 ; AG Hermann 2)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2022

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