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Stem Cells Transl Med. 2016 Dec;5(12):1644-1655. Epub 2016 Aug 2.

Induced Pluripotent Stem Cells for Disease Modeling and Evaluation of Therapeutics for Niemann-Pick Disease Type A.

Author information

1
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
2
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People's Republic of China.
3
Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
4
Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
5
Faculty of Health Sciences, University of Macau, Macau, People's Republic of China.
6
Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
7
Institute for Bioscience and Biotechnology Research, University of Maryland, College Park, Maryland, USA.
8
Fischell Department of Bioengineering, University of Maryland, College Park, Maryland, USA.
9
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
10
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA wzheng@mail.nih.gov.

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.

SIGNIFICANCE:

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.

KEYWORDS:

Acid sphingomyelinase; Cyclodextrin; Differentiated neural stem cells; Induced pluripotent stem cells; Niemann-Pick disease type A; α-Tocopherol; δ-Tocopherol

PMID:
27484861
PMCID:
PMC5189647
DOI:
10.5966/sctm.2015-0373
[Indexed for MEDLINE]
Free PMC Article

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