Extracellular vesicles for cardiac repair: A translational experience

The increasing recognition that stem cells transplanted in the myocardium act primarily through the paracrine activation of endogenous repair pathways mediated by the release of vesicular and soluble components has led to consider that these products could represent stand-alone therapeutics. Compared with the parental cells, they feature the major advantage of lacking immunogenicity, at least when the secretome is derived from cardiovascular progenitor cells (CPC). We then started a program aimed at testing this secretome in patients with chronic heart failure. The translational steps entailed the reprogramming of blood cells of an healthy donor into induced pluripotent stem cells (iPSC), their differentiation in CPC, the collection of the conditioned medium which has then been purified and concentrated by tangential flow filtration before cryopreservation of the scaled-out vials. The EV-enriched secretome has also been extensively quality-controlled. We have now started to test this extracellular vesicle-enriched secretome of CPC in severe non-ischemic dilated cardiomyopathy (SECRET-HF, NCT05774509). By July, 2024, 3 patient have been treated without safety issues. While this trial demonstrates the clinical translatability of the concept, several key questions remain to be addressed, particularly: Can the therapeutic effects of the secretome be recapitulated by a limited number of its components? What are the optimal dosing metrics? Is a cardiac-targeting of the secretome mandatory for achieving a therapeutic effect following a systemic delivery? Ongoing and future experimental and clinical studies should help addressing these issues, thereby allowing to more accurately positioning EV-enriched secretomes within the armamentarium of therapies against heart failure.