Hydrogel based induced pluripotent stem cell culture to model infant-onset neurodegenerative disease

The mucopolysaccharidoses (MPS) are a collection of disorders where a defect in lysosomal enzymes leads to intracellular and extracellular accumulation of glycosaminoglycans (GAGs). The abnormal structure and localisation of these macromolecules causes increasing problems with normal development, in some cases leading to significantly shortened life spans (<10 years) for babies who appear normal at birth. Although therapeutic application of recombinant enzymes has shown some benefit for specific MPS sub-types, issues with crossing the blood brain barrier mean that neurological degeneration remains a major issue. There is a clear need for improved environments to test therapeutics that model the increasing deposition of abnormal GAGs, in an in vitro setting that is relevant to the brain. A specific challenge is that commercially available 3D culture options are often composed of exactly the GAGs involved in MPS, making them unsuitable for a controlled test environment. Here we will combine complementary expertise; induced pluripotent stem cells (iPSCs) for disease modelling (Denning), the brain microenvironment (Coyle) and GAG biochemistry and 3D hydrogel culture (Merry) to achieve defined culture of MPS-modelling iPSCs and isogenic controls within peptide hydrogels move iPSC culture from 2D to 3D in a controlled and fully-defined environment.