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Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development

Sanfilippo syndrome type C (mucopolysaccharidosis IIIC) is an early-onset neurodegenerative lysosomal storage disorder, which is currently untreatable. The vast majority of studies focusing on disease mechanisms of Sanfilippo syndrome were performed on non-neural cells or mouse models, which present...

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Autores principales: Benetó, Noelia, Cozar, Monica, Castilla-Vallmanya, Laura, Zetterdahl, Oskar G., Sacultanu, Madalina, Segur-Bailach, Eulalia, García-Morant, María, Ribes, Antonia, Ahlenius, Henrik, Grinberg, Daniel, Vilageliu, Lluïsa, Canals, Isaac
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141323/
https://www.ncbi.nlm.nih.gov/pubmed/32121121
http://dx.doi.org/10.3390/jcm9030644
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author Benetó, Noelia
Cozar, Monica
Castilla-Vallmanya, Laura
Zetterdahl, Oskar G.
Sacultanu, Madalina
Segur-Bailach, Eulalia
García-Morant, María
Ribes, Antonia
Ahlenius, Henrik
Grinberg, Daniel
Vilageliu, Lluïsa
Canals, Isaac
author_facet Benetó, Noelia
Cozar, Monica
Castilla-Vallmanya, Laura
Zetterdahl, Oskar G.
Sacultanu, Madalina
Segur-Bailach, Eulalia
García-Morant, María
Ribes, Antonia
Ahlenius, Henrik
Grinberg, Daniel
Vilageliu, Lluïsa
Canals, Isaac
author_sort Benetó, Noelia
collection PubMed
description Sanfilippo syndrome type C (mucopolysaccharidosis IIIC) is an early-onset neurodegenerative lysosomal storage disorder, which is currently untreatable. The vast majority of studies focusing on disease mechanisms of Sanfilippo syndrome were performed on non-neural cells or mouse models, which present obvious limitations. Induced pluripotent stem cells (iPSCs) are an efficient way to model human diseases in vitro. Recently developed transcription factor-based differentiation protocols allow fast and efficient conversion of iPSCs into the cell type of interest. By applying these protocols, we have generated new neuronal and astrocytic models of Sanfilippo syndrome using our previously established disease iPSC lines. Moreover, our neuronal model exhibits disease-specific molecular phenotypes, such as increase in lysosomes and heparan sulfate. Lastly, we tested an experimental, siRNA-based treatment previously shown to be successful in patients’ fibroblasts and demonstrated its lack of efficacy in neurons. Our findings highlight the need to use relevant human cellular models to test therapeutic interventions and shows the applicability of our neuronal and astrocytic models of Sanfilippo syndrome for future studies on disease mechanisms and drug development.
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spelling pubmed-71413232020-04-10 Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development Benetó, Noelia Cozar, Monica Castilla-Vallmanya, Laura Zetterdahl, Oskar G. Sacultanu, Madalina Segur-Bailach, Eulalia García-Morant, María Ribes, Antonia Ahlenius, Henrik Grinberg, Daniel Vilageliu, Lluïsa Canals, Isaac J Clin Med Article Sanfilippo syndrome type C (mucopolysaccharidosis IIIC) is an early-onset neurodegenerative lysosomal storage disorder, which is currently untreatable. The vast majority of studies focusing on disease mechanisms of Sanfilippo syndrome were performed on non-neural cells or mouse models, which present obvious limitations. Induced pluripotent stem cells (iPSCs) are an efficient way to model human diseases in vitro. Recently developed transcription factor-based differentiation protocols allow fast and efficient conversion of iPSCs into the cell type of interest. By applying these protocols, we have generated new neuronal and astrocytic models of Sanfilippo syndrome using our previously established disease iPSC lines. Moreover, our neuronal model exhibits disease-specific molecular phenotypes, such as increase in lysosomes and heparan sulfate. Lastly, we tested an experimental, siRNA-based treatment previously shown to be successful in patients’ fibroblasts and demonstrated its lack of efficacy in neurons. Our findings highlight the need to use relevant human cellular models to test therapeutic interventions and shows the applicability of our neuronal and astrocytic models of Sanfilippo syndrome for future studies on disease mechanisms and drug development. MDPI 2020-02-28 /pmc/articles/PMC7141323/ /pubmed/32121121 http://dx.doi.org/10.3390/jcm9030644 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Benetó, Noelia
Cozar, Monica
Castilla-Vallmanya, Laura
Zetterdahl, Oskar G.
Sacultanu, Madalina
Segur-Bailach, Eulalia
García-Morant, María
Ribes, Antonia
Ahlenius, Henrik
Grinberg, Daniel
Vilageliu, Lluïsa
Canals, Isaac
Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development
title Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development
title_full Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development
title_fullStr Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development
title_full_unstemmed Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development
title_short Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development
title_sort neuronal and astrocytic differentiation from sanfilippo c syndrome ipscs for disease modeling and drug development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141323/
https://www.ncbi.nlm.nih.gov/pubmed/32121121
http://dx.doi.org/10.3390/jcm9030644
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