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

Mylinh Vu, Rong Li, Amanda Baskfield, Billy Lu, Atena Farkhondeh, Kirill Gorshkov, Omid Motabar, Jeanette Beers, Guokai Chen, Jizhong Zou, Angela J. Espejo-Mojica, Alexander Rodríguez-López, Carlos J. Alméciga-Díaz, Luis A. Barrera, Xuntian Jiang, Daniel S. Ory, Juan J. Marugan, Wei Zheng

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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.

Original languageEnglish
Article number152
JournalOrphanet Journal of Rare Diseases
Issue number1
StatePublished - Sep 17 2018


  • 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

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    Vu, M., Li, R., Baskfield, A., Lu, B., Farkhondeh, A., Gorshkov, K., Motabar, O., Beers, J., Chen, G., Zou, J., Espejo-Mojica, A. J., Rodríguez-López, A., Alméciga-Díaz, C. J., Barrera, L. A., Jiang, X., Ory, D. S., Marugan, J. J., & Zheng, W. (2018). Neural stem cells for disease modeling and evaluation of therapeutics for Tay-Sachs disease. Orphanet Journal of Rare Diseases, 13(1), [152].