TY - JOUR
T1 - Neural stem cells for disease modeling and evaluation of therapeutics for Tay-Sachs disease
AU - Vu, Mylinh
AU - Li, Rong
AU - Baskfield, Amanda
AU - Lu, Billy
AU - Farkhondeh, Atena
AU - Gorshkov, Kirill
AU - Motabar, Omid
AU - Beers, Jeanette
AU - Chen, Guokai
AU - Zou, Jizhong
AU - Espejo-Mojica, Angela J.
AU - Rodríguez-López, Alexander
AU - Alméciga-Díaz, Carlos J.
AU - Barrera, Luis A.
AU - Jiang, Xuntian
AU - Ory, Daniel S.
AU - Marugan, Juan J.
AU - Zheng, Wei
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/9/17
Y1 - 2018/9/17
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85053538927
UR - https://www.scopus.com/inward/citedby.url?scp=85053538927&partnerID=8YFLogxK
U2 - 10.1186/s13023-018-0886-3
DO - 10.1186/s13023-018-0886-3
M3 - Research Article
C2 - 30220252
AN - SCOPUS:85053538927
SN - 1750-1172
VL - 13
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
IS - 1
M1 - 152
ER -
