Metabolomics as a tool for developing therapies in an endothelial cell model of congenital disorders of glycosylation

Congenital disorders of glycosylation (CDG) are severe multisystemic inborn errors of metabolism. For most of these orphan diseases, there is only supportive therapy, therefor constituting an unmet medical need. In PMM2-CDG, the most frequent CDG, despite its genetic characterization and clarification of enzymatic dysfunction, there is insufficient insight in the pathophysiology to adequately develop therapies. In current project we will apply a refreshing broad approach, by performing transcriptomics, untargeted metabolomics in a novel PMM2 cell model based on endothelial cells (ECs) that are a key actor in the pathophysiology. These models are constructed though pharmacologic inhibition and PMM2 knockdown in human umbilical vein ECs or in blood outgrowth ECs, isolated directly from the CDG patients. All relevant endothelial functions (e.g. barrier function, EC dysfunction, role in inflammation) as well as the rewiring of the metabolic pathways and changes in cellular milieu, as identified through tracer metabolomics, will be studied in detail using our own established methods.