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 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.
Highlights
To date, there is no treatment for the neurological symptoms of SanLysosomal storage disorders (LSDs) are a group of rare inherited metabolic diseases caused by deficiencies in lysosomal enzymes leading to impaired recycling of macromolecules and alteration of the endolysosomal system [1]
Sanfilippo syndrome type C is caused by a deficiency in an enzyme located in the lysosomal membrane, heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT, EC 2.3.1.78) [6], which is encoded by the HGSNAT gene
We identified a tendency towards increased levels of heparan sulfate (HS) in disease induced neurons (iNs) compared to the healthy control, suggesting that iNs displayed one of the major cellular phenotypes associated with Sanfilippo syndrome (Figure 5)
Summary
There is no treatment for the neurological symptoms of SanLysosomal storage disorders (LSDs) are a group of rare inherited metabolic diseases caused by deficiencies in lysosomal enzymes leading to impaired recycling of macromolecules and alteration of the endolysosomal system [1]. Sanfilippo syndrome type C is caused by a deficiency in an enzyme located in the lysosomal membrane, heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT, EC 2.3.1.78) [6], which is encoded by the HGSNAT gene. This gene is in the pericentromeric region of chromosome 8 (8p11.2–8p11.1) and has 18 exons [7,8]. Some promising results have been obtained in a mouse model using a novel AAV with a modified capsid [18] Another interesting therapeutic approach for LSDs is substrate reduction therapy (SRT) to decrease the synthesis of the molecule that cannot be correctly degraded. Given the neurological symptoms seen in patients, it is crucial to study SRT in relevant human neural cells
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