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Orphanet J Rare Dis. 2018 Sep 17;13(1):152. doi: 10.1186/s13023-018-0886-3.

Neural stem cells for disease modeling and evaluation of therapeutics for Tay-Sachs disease.

Author information

1
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
2
Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
3
Faculty of Health Sciences, University of Macau, Macau, People's Republic of China.
4
Institute for the Study of Inborn Errors of Metabolism, Faculty of Sciences, Pontificia Universidad Javeriana, Bogotá, Colombia.
5
Chemistry Department, Faculty of Science, Pontificia Universidad Javeriana, Bogotá, Colombia.
6
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO, USA.
7
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA. wzheng@mail.nih.gov.

Abstract

BACKGROUND:

Tay-Sachs disease (TSD) is a rare neurodegenerative disorder caused by autosomal recessive mutations in the HEXA gene on chromosome 15 that encodes β-hexosaminidase. Deficiency in HEXA results in accumulation of GM2 ganglioside, a glycosphingolipid, in lysosomes. Currently, there is no effective treatment for TSD.

RESULTS:

We generated induced pluripotent stem cells (iPSCs) from two TSD patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). The TSD neural stem cells exhibited a disease phenotype of lysosomal lipid accumulation. The Tay-Sachs disease NSCs were then used to evaluate the therapeutic effects of enzyme replacement therapy (ERT) with recombinant human Hex A protein and two small molecular compounds: hydroxypropyl-β-cyclodextrin (HPβCD) and δ-tocopherol. Using this disease model, we observed reduction of lipid accumulation by employing enzyme replacement therapy as well as by the use of HPβCD and δ-tocopherol.

CONCLUSION:

Our results demonstrate that the Tay-Sachs disease NSCs possess the characteristic phenotype to serve as a cell-based disease model for study of the disease pathogenesis and evaluation of drug efficacy. The enzyme replacement therapy with recombinant Hex A protein and two small molecules (cyclodextrin and tocopherol) significantly ameliorated lipid accumulation in the Tay-Sachs disease cell model.

KEYWORDS:

Cyclodextrin; Drug discovery; Enzyme replacement therapy; GM2 gangliosidosis; HPβCD; Hexosaminidase A; High throughput screening; Induced pluripotent stem cells; Neural stem cells; Tay-Sachs disease; δ-tocopherol

PMID:
30220252
PMCID:
PMC6139903
DOI:
10.1186/s13023-018-0886-3
[Indexed for MEDLINE]
Free PMC Article

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