Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development.
Noelia BenetóMonica CozarLaura Castilla-VallmanyaOskar G ZetterdahlMadalina SacultanuEulalia Segur-BailachMaría García-MorantAntonia RibesHenrik AhleniusDaniel GrinbergLluïsa VilageliuIsaac CanalsPublished in: Journal of clinical medicine (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.
Keyphrases
- hyaluronic acid
- induced pluripotent stem cells
- early onset
- transcription factor
- endothelial cells
- case report
- ejection fraction
- spinal cord
- late onset
- mouse model
- drug delivery
- oxidative stress
- physical activity
- cerebral ischemia
- cell death
- brain injury
- cell proliferation
- pluripotent stem cells
- endoplasmic reticulum stress
- single molecule
- combination therapy