Neural stem cells for disease modeling of Wolman disease and evaluation of therapeutics

Orphanet J Rare Dis. 2017 Jun 28;12(1):120. doi: 10.1186/s13023-017-0670-9.


Background: Wolman disease (WD) is a rare lysosomal storage disorder that is caused by mutations in the LIPA gene encoding lysosomal acid lipase (LAL). Deficiency in LAL function causes accumulation of cholesteryl esters and triglycerides in lysosomes. Fatality usually occurs within the first year of life. While an enzyme replacement therapy has recently become available, there is currently no small-molecule drug treatment for WD.

Results: We have generated induced pluripotent stem cells (iPSCs) from two WD patient dermal fibroblast lines and subsequently differentiated them into neural stem cells (NSCs). The WD NSCs exhibited the hallmark disease phenotypes of neutral lipid accumulation, severely deficient LAL activity, and increased LysoTracker dye staining. Enzyme replacement treatment dramatically reduced the WD phenotype in these cells. In addition, δ-tocopherol (DT) and hydroxypropyl-beta-cyclodextrin (HPBCD) significantly reduced lysosomal size in WD NSCs, and an enhanced effect was observed in DT/HPBCD combination therapy.

Conclusion: The results demonstrate that these WD NSCs are valid cell-based disease models with characteristic disease phenotypes that can be used to evaluate drug efficacy and screen compounds. DT and HPBCD both reduce LysoTracker dye staining in WD cells. The cells may be used to further dissect the pathology of WD, evaluate compound efficacy, and serve as a platform for high-throughput drug screening to identify new compounds for therapeutic development.

Keywords: Cell-based disease model; Induced pluripotent stem cells; Lysosomal storage disease; Neural stem cells; Wolman disease.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin / pharmacology
  • Blotting, Western
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Cholesterol / metabolism
  • Humans
  • Immunohistochemistry
  • Lipoproteins, LDL / pharmacology
  • Lysosomal-Associated Membrane Protein 2 / metabolism
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / metabolism*
  • Skin / cytology
  • Skin / metabolism
  • Tocopherols / pharmacology
  • Wolman Disease / metabolism*


  • LAMP2 protein, human
  • Lipoproteins, LDL
  • Lysosomal-Associated Membrane Protein 2
  • 2-Hydroxypropyl-beta-cyclodextrin
  • Cholesterol
  • Tocopherols