Establishment of iPSC derived 2D and 3D Niemann Pick Disease Type C2 Disease Models and Therapeutics Evaluation

Authors

• M Xu
• Y Shu
• C Chen
• W Zheng

Abstract

Niemann Pick Disease Type C2 (NPC2) is a rare autosomal recessive disorder caused by mutations in NPC2 genes, leading to cholesterol accumulation in lysosomes and subsequent neuronal degeneration. Creating neural cell lines, particularly human neurons, is pivotal for studying NPC pathogenesis and drug development. However, challenges persist in generating such lines, hindering treatment progress. Here, we establish human induced pluripotent stem cells (iPSCs) from NPC2 patient fibroblasts, differentiating them into neural stem cells and neuronal organoids for disease modeling. NPC2 neural stem cells and neurons from organoids display cholesterol accumulation and enlarged lysosomes. Treatment with Hydroxypropyl-β-cyclodextrin (HPBCD) and NPC2 protein reduces cholesterol accumulation and normalizes lysosome size, indicating the potential of iPSC-derived models for drug screening and efficacy evaluation in NPC2 therapy.

Scientific Focus Area: Stem Cell Biology

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