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

Benetó, Noelia ; Cozar, Monica ; Castilla-Vallmanya, Laura LU ; Zetterdahl, Oskar G LU ; Sacultanu, Madalina LU ; Segur-Bailach, Eulalia ; García-Morant, María ; Ribes, Antonia ; Ahlenius, Henrik LU and Grinberg, Daniel , et al. (2020) In Journal of Clinical Medicine 9(3).
Abstract

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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Clinical Medicine
volume
9
issue
3
publisher
MDPI AG
external identifiers
  • scopus:85085525479
  • pmid:32121121
ISSN
2077-0383
DOI
10.3390/jcm9030644
language
English
LU publication?
yes
id
5f5e43f1-9efd-4252-b9f7-aaab1e785bd2
date added to LUP
2021-04-15 10:10:17
date last changed
2024-03-07 22:27:39
@article{5f5e43f1-9efd-4252-b9f7-aaab1e785bd2,
  abstract     = {{<p>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.</p>}},
  author       = {{Benetó, Noelia and Cozar, Monica and Castilla-Vallmanya, Laura and Zetterdahl, Oskar G and Sacultanu, Madalina and Segur-Bailach, Eulalia and García-Morant, María and Ribes, Antonia and Ahlenius, Henrik and Grinberg, Daniel and Vilageliu, Lluïsa and Canals, Isaac}},
  issn         = {{2077-0383}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{3}},
  publisher    = {{MDPI AG}},
  series       = {{Journal of Clinical Medicine}},
  title        = {{Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development}},
  url          = {{http://dx.doi.org/10.3390/jcm9030644}},
  doi          = {{10.3390/jcm9030644}},
  volume       = {{9}},
  year         = {{2020}},
}