title: Niemann-Pick Disease Type C: Induced Pluripotent Stem Cell-Derived Neuronal Cells for Modeling Neural Disease and Evaluating Drug Efficacy.
abstract: Niemann-Pick disease type C (NPC) is a rare neurodegenerative disorder caused by recessive mutations in the NPC1 or NPC2 gene that result in lysosomal accumulation of unesterified cholesterol in patient cells. Patient fibroblasts have been used for evaluation of compound efficacy, although neuronal degeneration is the hallmark of NPC disease. Here, we report the application of human NPC1 neural stem cells as a cell-based disease model to evaluate nine compounds that have been reported to be efficacious in the NPC1 fibroblasts and mouse models. These cells are differentiated from NPC1 induced pluripotent stem cells and exhibit a phenotype of lysosomal cholesterol accumulation. Treatment of these cells with hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, and δ-tocopherol significantly ameliorated the lysosomal cholesterol accumulation. Combined treatment with cyclodextrin and δ-tocopherol shows an additive or synergistic effect that otherwise requires 10-fold higher concentration of cyclodextrin alone. In addition, we found that hydroxypropyl-β-cyclodextrin is much more potent and efficacious in the NPC1 neural stem cells compared to the NPC1 fibroblasts. Miglustat, suberoylanilide hydroxamic acid, curcumin, lovastatin, pravastatin, and rapamycin did not, however, have significant effects in these cells. The results demonstrate that patient-derived NPC1 neural stem cells can be used as a model system for evaluation of drug efficacy and study of disease pathogenesis.
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Daozhan
authors.initials: D
authors.lastname: Yu
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Manju
authors.initials: M
authors.lastname: Swaroop
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Mengqiao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Electron Microscopy Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baxa
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Rongze
authors.initials: R
authors.lastname: Yang
authors.affiliation: Life Technologies, Frederick, MD, USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Comparative Medicine Program, Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Turhan
authors.initials: T
authors.lastname: Coksaygan
authors.affiliation: Life Technologies, Frederick, MD, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: DeTolla
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Marugan
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: McKew
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA Geriatrics Research and Education Clinical Center, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Gong
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA dgong@medicine.umaryland.edu wzheng@mail.nih.gov.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003505:Cyclodextrins / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004357:Drug Synergism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D058953:Neural Stem Cells / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy / Q000473:pathology*; D024505:Tocopherols / Q000494:pharmacology
chemical_list: D003505:Cyclodextrins; D002784:Cholesterol; C479072:delta-tocopherol; D024505:Tocopherols
keywords: NPC1; Niemann–Pick disease type C; cyclodextrin; differentiated neurons; drug combination therapy; induced pluripotent stem cells; δ-tocopherol