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Open AccessArticle

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

1
Department Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, CIBERER, IBUB, IRSJD, E-08028 Barcelona, Spain
2
Stem Cells, Aging and Neurodegeneration Group, Department of Clinical Sciences, Neurology, Lund Stem Cell Center, Lund University, SE-22184 Lund, Sweden
3
Department of Biochemistry and Molecular Genetics, Hospital Clinic de Barcelona, CIBERER, IDIBAPS, E-08028 Barcelona, Spain
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(3), 644; https://doi.org/10.3390/jcm9030644
Received: 31 January 2020 / Revised: 21 February 2020 / Accepted: 26 February 2020 / Published: 28 February 2020
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. View Full-Text
Keywords: sanfilippo syndrome; mucopolysaccharidosis III; lysosomal storage disorders; induced pluripotent stem cells; neuronal differentiation; astrocyte differentiation; transcription factor-based differentiation; lysosomes; siRNAs; substrate reduction therapy sanfilippo syndrome; mucopolysaccharidosis III; lysosomal storage disorders; induced pluripotent stem cells; neuronal differentiation; astrocyte differentiation; transcription factor-based differentiation; lysosomes; siRNAs; substrate reduction therapy
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Benetó, N.; Cozar, M.; Castilla-Vallmanya, L.; Zetterdahl, O.G.; Sacultanu, M.; Segur-Bailach, E.; García-Morant, M.; Ribes, A.; Ahlenius, H.; Grinberg, D.; Vilageliu, L.; Canals, I. Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development. J. Clin. Med. 2020, 9, 644.

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