In vivo cardiac targeting of glycan-engineered extracellular vesicles – Exoglyc

The objective of this project is to develop a treatment of heart failure (HF) based on intravenous injections of the extracellular vesicle (EV)-enriched secretome of cardiovascular progenitor cells. The rationale is that the primary mechanism of action of the cells is the paracrine activation of endogenous repair pathways, largely contributed by the EV that they secrete. The intravenous route has been selected primarily because of its lack of invasiveness which opens the possibility of repeating injections. However, EV delivered by this approach are primarily sequestered in lungs, spleen and liver with few of them reaching the heart. Even though this peripheral trapping can induce indirect cardioprotective effects through a modulation of systemic immune-inflammatory responses, experimental studies suggest that this benefit could be optimized by increasing directly the presence of EV in the target myocardial tissue. So far, this cardiac targeting of EV has been achieved by chemical or genetic manipulations of the EV parental cells or of EV directly but although these approaches have been efficacious, their complexity may hamper their clinical implementation. Our objectives are thus (1) to leverage the presence, at the surface of the EV, of glycans amenable to a chemical modification (exofucosylation) allowing them to express a ligand of E-selectin (sialyl Lewis X). This approach has a dual rationale: (i) E-selectin is an adhesion receptor activated on the endothelium in an inflammatory environment, which is a hallmark of HF, and as such it looks a logical target for enhancing homing of EV towards the heart, and (ii) exofucosylation is a technique the feasibility, safety and efficacy of which have already been established and validated in the clinics; (2) to document the biodistribution of these glycan-engineered EV following their direct radio-labeling by gallium-oxine and tracking of their fate by positron emission tomography, and (3) to assess the functional and histological consequences of this cardiac targeting of glycan-engineered EV following their intravenous injection in a murine model of postinfarction left ventricular dysfunction.