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

Orphanet Journal of Rare Diseases

Jeanette Beers¹  Jizhong Zou¹  Guokai Chen¹  Daniel S. Ory²  Xuntian Jiang²  Carlos J. Alméciga-Díaz³  Alexander Rodríguez-López³  Angela J. Espejo-Mojica³  Luis A. Barrera³  Rong Li⁴  Juan J. Marugan⁴  Billy Lu⁴  Wei Zheng⁴  Omid Motabar⁴  Kirill Gorshkov⁴  Mylinh Vu⁴  Amanda Baskfield⁴  Atena Farkhondeh⁴ 

[1] Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health;Diabetic Cardiovascular Disease Center, Washington University School of Medicine;Institute for the Study of Inborn Errors of Metabolism, Faculty of Sciences, Pontificia Universidad Javeriana;National Center for Advancing Translational Sciences, National Institutes of Health;

关键词: Tay-Sachs disease;    Induced pluripotent stem cells;    Neural stem cells;    Cyclodextrin;    HPβCD;    δ-tocopherol;   

DOI  :  10.1186/s13023-018-0886-3

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown