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Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses

BACKGROUND: Infantile and late infantile neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases affecting the central nervous system (CNS). The infantile NCL (INCL) is caused by mutations in the PPT1 gene and late-infantile NCL (LINCL) is due to mutations in the TPP1 gene. Deficiency i...

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Autores principales: Sima, Ni, Li, Rong, Huang, Wei, Xu, Miao, Beers, Jeanette, Zou, Jizhong, Titus, Steven, Ottinger, Elizabeth A., Marugan, Juan J., Xie, Xing, Zheng, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891977/
https://www.ncbi.nlm.nih.gov/pubmed/29631617
http://dx.doi.org/10.1186/s13023-018-0798-2
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author Sima, Ni
Li, Rong
Huang, Wei
Xu, Miao
Beers, Jeanette
Zou, Jizhong
Titus, Steven
Ottinger, Elizabeth A.
Marugan, Juan J.
Xie, Xing
Zheng, Wei
author_facet Sima, Ni
Li, Rong
Huang, Wei
Xu, Miao
Beers, Jeanette
Zou, Jizhong
Titus, Steven
Ottinger, Elizabeth A.
Marugan, Juan J.
Xie, Xing
Zheng, Wei
author_sort Sima, Ni
collection PubMed
description BACKGROUND: Infantile and late infantile neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases affecting the central nervous system (CNS). The infantile NCL (INCL) is caused by mutations in the PPT1 gene and late-infantile NCL (LINCL) is due to mutations in the TPP1 gene. Deficiency in PPT1 or TPP1 enzyme function results in lysosomal accumulation of pathological lipofuscin-like material in the patient cells. There is currently no small-molecular drug treatment for NCLs. RESULTS: We have generated induced pluripotent stem cells (iPSC) from three patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). Using these new disease models, we evaluated the effect of δ-tocopherol (DT) and hydroxypropyl-β-cyclodextrin (HPBCD) with the enzyme replacement therapy as the control. Treatment with the relevant recombinant enzyme or DT significantly ameliorated the lipid accumulation and lysosomal enlargement in the disease cells. A combination therapy of δ-tocopherol and HPBCD further improved the effect compared to that of either drug used as a single therapy. CONCLUSION: The results demonstrate that these patient iPSC derived NCL NSCs are valid cell- based disease models with characteristic disease phenotypes that can be used for study of disease pathophysiology and drug development. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13023-018-0798-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-58919772018-04-11 Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses Sima, Ni Li, Rong Huang, Wei Xu, Miao Beers, Jeanette Zou, Jizhong Titus, Steven Ottinger, Elizabeth A. Marugan, Juan J. Xie, Xing Zheng, Wei Orphanet J Rare Dis Research BACKGROUND: Infantile and late infantile neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases affecting the central nervous system (CNS). The infantile NCL (INCL) is caused by mutations in the PPT1 gene and late-infantile NCL (LINCL) is due to mutations in the TPP1 gene. Deficiency in PPT1 or TPP1 enzyme function results in lysosomal accumulation of pathological lipofuscin-like material in the patient cells. There is currently no small-molecular drug treatment for NCLs. RESULTS: We have generated induced pluripotent stem cells (iPSC) from three patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). Using these new disease models, we evaluated the effect of δ-tocopherol (DT) and hydroxypropyl-β-cyclodextrin (HPBCD) with the enzyme replacement therapy as the control. Treatment with the relevant recombinant enzyme or DT significantly ameliorated the lipid accumulation and lysosomal enlargement in the disease cells. A combination therapy of δ-tocopherol and HPBCD further improved the effect compared to that of either drug used as a single therapy. CONCLUSION: The results demonstrate that these patient iPSC derived NCL NSCs are valid cell- based disease models with characteristic disease phenotypes that can be used for study of disease pathophysiology and drug development. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13023-018-0798-2) contains supplementary material, which is available to authorized users. BioMed Central 2018-04-10 /pmc/articles/PMC5891977/ /pubmed/29631617 http://dx.doi.org/10.1186/s13023-018-0798-2 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Sima, Ni
Li, Rong
Huang, Wei
Xu, Miao
Beers, Jeanette
Zou, Jizhong
Titus, Steven
Ottinger, Elizabeth A.
Marugan, Juan J.
Xie, Xing
Zheng, Wei
Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses
title Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses
title_full Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses
title_fullStr Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses
title_full_unstemmed Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses
title_short Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses
title_sort neural stem cells for disease modeling and evaluation of therapeutics for infantile (cln1/ppt1) and late infantile (cln2/tpp1) neuronal ceroid lipofuscinoses
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891977/
https://www.ncbi.nlm.nih.gov/pubmed/29631617
http://dx.doi.org/10.1186/s13023-018-0798-2
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