Towards treatments 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.
Identified therapies will be tested through in vitro and ex vivo through
nutritional therapy to address this unmet medical need. In the last
stage of this project, this will be confirmed through clinical trials.
Additional CDG (e.g. SLC35A2-CDG and TMEM165-CDG) will be
further studied in a similar fashion.