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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin / therapeutic use
  • Cell Differentiation / physiology
  • Cell Line
  • Enzyme Replacement Therapy / methods
  • Female
  • Fluorescent Antibody Technique
  • Gangliosidoses, GM2 / metabolism
  • Hexosaminidase A / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / physiology
  • Male
  • Microsatellite Repeats / genetics
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / physiology
  • Pichia / metabolism
  • Tandem Mass Spectrometry
  • Tay-Sachs Disease / drug therapy*
  • Tay-Sachs Disease / genetics
  • Tay-Sachs Disease / metabolism
  • Tay-Sachs Disease / therapy*
  • Tocopherols / therapeutic use

Substances

  • 2-Hydroxypropyl-beta-cyclodextrin
  • Hexosaminidase A
  • delta-tocopherol
  • Tocopherols