Breaking BBB by protein engineering and glycodesign

Polysialic acid (PolySia) is a rare a2,8-linked sialic acid homopolymer with extremely high protein selectivity, involved in multiple activities, like control of cell-cell interactions and cell migration. It also occurs in bacteria as a capsular polysaccharide. Often, its function depends on the degree of polymerization (DP), but there is no solid knowledge about structure/ function relation. A major obstacle in the study of polySia is its low availability. A major challenge in effectively treating neurological diseases is the low permeability of drugs across the blood-brain barrier (BBB). To overcome this challenge, this project will mimic a natural mechanism by which neuroinvasive bacteria evade the human immune system and cross the BBB. Neisseria meningitidis for example cross the BBB via their capsular polysaccharide PolySia. Here, we apply protein- and glycoengineering strategies to establish a plant expression system that synthesizes low-molecular-weight polySia (LMW-PolySia, DP20-30). The approach utilizes extensive cross-phylum genetics, i.e., transfer and expression of genetic material in plants from organisms with large evolutionary distance (e.g., bacteria, humans). The interaction of several foreign building blocks is designed to induce the LMW-polySia pathway in plants. Finally, protein-bound LMW-polySia will be tested for its ability to enter neuronal tissue using in vitro model.