Nature of the project:

Project funded by the French Research Agency

Summary of the project:

The objective of this project is to develop a new biological treatment for severe heart failure, based on the controlled biomaterial-mediated administration of extracellular vesicles (EV) secreted by cardiovascular progenitor cells. The underlying rationale is that the benefits of stem cells transplanted in the myocardium are not related to their structural integration but rather to the secretion of factors that harness endogenous repair pathways and are clustered in extracellular vesicles (EV) which can transfer their biological cargo (noncoding nucleic acids, proteins, lipids) into target cells.

Several experimental studies have shown in various disease models (myocardial infarction, limb ischemia, renal insufficiency, retinal injury, stroke) that the protective effects of stem cells could be largely, not to say fully, recapitulated by the sole administration of the EV that they release. These data account for the growing interest in EV as cell-mimetic therapeutics because of their advantages over cell transplantation (possibility of large-scale production, consistent characterization and off-the-shelf storage and availability) which bring them closer to a pharma-type development model, which an attendant decrease in costs and thus broader clinical applications.

Our group has first shown, in a mouse model of chronic postinfarction cardiac failure, that the functional benefits of human embryonic stem cell (ESC)-derived cardiovascular progenitors – similar to those tested in an ongoing clinical trial – were duplicated by the sole administration of the EV they release. We have then confirmed these results with EV derived from cardiovascular progenitor cells differentiated from induced pluripotent stem cells (iPSC). In this project, these iPSC will be the source of the cardiovascular progenitor cells; the oncologic risk of using iPSC is no longer relevant because the iPSC-derived progeny is not intended for in vivo transplantation but only serves as an in vitro EV-producing "biofactory".

This project entails 3 major consecutive tasks: (1) the expansion of the cardiovascular progenitors in a bioreactor to achieve large-scale cell production in a controlled environment; (2) the isolation of EV from the conditioned medium secreted by the cells; it will be based on tangential filtration and require to select a membrane with a molecular weight allowing to retain the most functionally efficacious fraction, as assessed by the in vitro viability and angiogenesis tests that we have developed; and (3) the functionalization of a biomaterial with the purified EV to allow their controlled release following intramyocardial delivery (by catheter or surgically). Our first choice is hyaluronic acid which has been previously shown successful for cell and drug delivery. The ultimate objective of the project is thus the set-up of a bank of EV which can be fully qualified on the basis of the usual criteria (identity, purity, potency, sterility) with the subsequent controlled-release delivery of these EV by functionalization of the hydrogel.

Preclinical studies of cells and EV will be performed in our laboratory (UMR 970); the INSERM U1008 (Facultés de Pharmacie, Médecine et Chirurgie Dentaire de Lille) and the Institut Galien Paris-Sud, UMR CNRS8612 will be in charge of the development of the polymer and is functionalization modalities. The final product assembly will be made under Good Manufacturing Practice conditions in the platform of the Département de Biothérapies Cellulaires et Tissulaire (Hôpital Saint-Louis). Thus, the consortium has been set so as to combine complementary expertises in the fields of cardiology and cardiac surgery, cell biology, material science, experimental studies and production of clinical lots of biological therapeutics, so as to maximize the probability of a successful outcome.

For more information: https://anr.fr/Projet-ANR-17-CE18-0003

Coordinator

INSERM U970, Hôpital Européen Georges Pompidou, Paris, France (Philippe Menasché)

Partners

INSERM U970, Hôpital Européen Georges Pompidou, Paris, France (coordinator)

CNRS UMR 8612, Institut Galien Paris-Sud, France

INSERM U1008, University of Lille, France

Unité de Thérapie Cellulaire, Hôpital Saint-Louis, France

Duration of the project

3 years