martes, 18 de septiembre de 2018

Neural stem cells for disease modeling and evaluation of therapeutics for Tay-Sachs disease | Orphanet Journal of Rare Diseases | Full Text

Neural stem cells for disease modeling and evaluation of therapeutics for Tay-Sachs disease | Orphanet Journal of Rare Diseases | Full Text

Orphanet Journal of Rare Diseases

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

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Orphanet Journal of Rare Diseases201813:152
  • Received: 21 November 2017
  • Accepted: 6 August 2018
  • Published: 

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

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

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