This project will establish robust protocols for site-directed mutagenesis of glycans in mammalian cells.
The project will develop cellular inhibitors of glycosyltransferases to enable manipulation of the glycosylation of glycoproteins.
The aim is to provide designed glycosylation for recombinant glycoprotein prodduction of biologics and for efficient cell therapy (CAR-T).
The inhibitors can be implemented to next generation precision medicine in for instance cancer treatment.
Participants
More about the project
Our vision is to have impact through the precise manipulation of the glycans (carbohydrates) on cells and recombinant glycoproteins that will enable the discovery and production of the next generation of therapies for cancer, neurodegeneration and other disease families.
The glycans that are present on most proteins and cells have a substantial impact on their biological functions, yet the untemplated nature of their synthesis leads to inherent heterogeneity in both their structure and activity. This heterogeneity is very difficult to control, making it impossible to generate defined glycan ensembles with optimal activity using current technology.
The project will adopt a radically new approach to manipulate cellular glycans. We will develop the delivery of computationally defined mixtures of enzyme-specific inhibitors to the site of glycan biosynthesis in the cell to tune the activity of glycosyltransferases.
Our approach, termed Inhibitor-Mediated Programmingering of Glykoforms (IMProGlyco) will provide an effective strategy to manipulate the glycosylation machinery and thereby generate proteins with defined ensembles of glycans. It will enable the production of precision glycan engineered therapeutic proteins and vaccines.
Moreover, shaping cellular glycan profiles will aid discovery science to uncover glycan functions and improve therapeutic cells, such as those used in Chimeric Antigen Receptors cell Therapy (CAR-T). Our technology will be adaptable and expandable into other cell types and organisms allowing glycan shaping in all areas of eukaryotic cell biology to enable new biotechnological applications and fundamental studies of biology.
