title: Induced Pluripotent Stem Cells for Disease Modeling and Evaluation of Therapeutics for Niemann-Pick Disease Type A.
abstract: : Niemann-Pick disease type A (NPA) is a lysosomal storage disease caused by mutations in the SMPD1 gene that encodes acid sphingomyelinase (ASM). Deficiency in ASM function results in lysosomal accumulation of sphingomyelin and neurodegeneration. Currently, there is no effective treatment for NPA. To accelerate drug discovery for treatment of NPA, we generated induced pluripotent stem cells from two patient dermal fibroblast lines and differentiated them into neural stem cells. The NPA neural stem cells exhibit a disease phenotype of lysosomal sphingomyelin accumulation and enlarged lysosomes. By using this disease model, we also evaluated three compounds that reportedly reduced lysosomal lipid accumulation in Niemann-Pick disease type C as well as enzyme replacement therapy with ASM. We found that α-tocopherol, δ-tocopherol, hydroxypropyl-β-cyclodextrin, and ASM reduced sphingomyelin accumulation and enlarged lysosomes in NPA neural stem cells. Therefore, the NPA neural stem cells possess the characteristic NPA disease phenotype that can be ameliorated by tocopherols, cyclodextrin, and ASM. Our results demonstrate the efficacies of cyclodextrin and tocopherols in the NPA cell-based model. Our data also indicate that the NPA neural stem cells can be used as a new cell-based disease model for further study of disease pathophysiology and for high-throughput screening to identify new lead compounds for drug development.
  
  
  
  Currently, there is no effective treatment for Niemann-Pick disease type A (NPA). To accelerate drug discovery for treatment of NPA, NPA-induced pluripotent stem cells were generated from patient dermal fibroblasts and differentiated into neural stem cells. By using the differentiated NPA neuronal cells as a cell-based disease model system, α-tocopherol, δ-tocopherol, and hydroxypropyl-β-cyclodextrin significantly reduced sphingomyelin accumulation in these NPA neuronal cells. Therefore, this cell-based NPA model can be used for further study of disease pathophysiology and for high-throughput screening of compound libraries to identify lead compounds for drug development.
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.|Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.|Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Miao
authors.initials: M
authors.lastname: Xu
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.|Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Dai
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Beers
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.|Faculty of Health Sciences, University of Macau, Macau, People's Republic of China.
authors.forename: Guokai
authors.initials: G
authors.lastname: Chen
authors.affiliation: Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Ferri
authors.initials: F
authors.lastname: Soheilian
authors.affiliation: Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baxa
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Mengqiao
authors.initials: M
authors.lastname: Wang
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Marugan
authors.affiliation: Institute for Bioscience and Biotechnology Research, University of Maryland, College Park, Maryland, USA.|Fischell Department of Bioengineering, University of Maryland, College Park, Maryland, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Muro
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People's Republic of China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Roscoe
authors.initials: R
authors.lastname: Brady
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA wzheng@mail.nih.gov.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000648:ultrastructure; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008954:Models, Biological; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D052536:Niemann-Pick Disease, Type A / Q000473:pathology* / Q000628:therapy*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D024505:Tocopherols / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000494:pharmacology; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D013109:Sphingomyelins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D013108:Sphingomyelin Phosphodiesterase; D024502:alpha-Tocopherol; C479072:delta-tocopherol; D024505:Tocopherols
keywords: Acid sphingomyelinase; Cyclodextrin; Differentiated neural stem cells; Induced pluripotent stem cells; Niemann-Pick disease type A; α-Tocopherol; δ-Tocopherol