jueves, 29 de junio de 2017

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

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



Biomed Central



Orphanet Journal of Rare Diseases

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

Contributed equally
Orphanet Journal of Rare Diseases201712:120
DOI: 10.1186/s13023-017-0670-9
Received: 2 December 2016
Accepted: 13 June 2017
Published: 28 June 2017

Abstract

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

Wolman disease Lysosomal storage disease Induced pluripotent stem cells Neural stem cells Cell-based disease model

No hay comentarios:

Publicar un comentario