CARDIOPHAGY · Tissue-specific induction of autophagy as an innovative therapeutic strategy in cardiovascular and metabolic disease.

Western-style diets are hypercaloric and characterized by high fat and high sugar content. They are responsible for an epidemic of cardiovascular disease, including atherosclerosis (AS), and metabolic disorders, including Non-Alcoholic Fatty Liver Disease (NAFLD). The European population is becoming increasingly exposed to these disorders, for which the only available therapeutic option is lifestyle modification. This typically involves dietary changes and physical activity, but patient compliance with these measures tends to be suboptimal. Pharmacological treatment options could therefore have significant potential to improve patient perspectives.With this respect, pharmacological induction of autophagy is intensively studied. Autophagy is the main detoxification and recycling mechanism of cells, and it has been shown to become dysfunctional in AS and NAFLD. Small molecules that can stimulate the process have been demonstrated to treat the diseases in animal models. However, all known autophagy-inducing molecules lack specificity, and this is suspected to cause systemic toxicity during chronic application in humans. In this proposal, we deliver molecules that avoid systemic exposure by targeting them specifically to disease-relevant tissues. First, potent autophagy inducers will be chemically linked to selected homing peptides that we hypothesize to deliver the molecules to dysfunctional vascular endothelial cells in atherosclerosis. Similarly, we hypothesize that triantennary N-acetyl galactosamine (GN3) can guide autophagy inducers to liver cells in the context of NAFLD. All molecules that are prepared in this project will be first studied in cells: both autophagy induction potential and tissue targeting will be evaluated thoroughly. For the best molecule prepared (either endothelial- or liver-targeted), in vivo proof-of-concept will be delivered. In this way, the proposal's potential to deliver new, relevant drugs will be maximally valorized.