CARdiac Mesenchymal Extracellular Vesicles (CARMEV) for prevention of ischemic heart failure

Purpose and goal

We have succeeded in creating a GMP-adapted production of extracellular vesicles (EVs) from both "human prenatal cardiac mesenchymal stromal cells" (hpcMSCs) and bone marrow MSCs (BM-MSCs), which have been evaluated for their effect in preventing heart failure after a myocardial infarction in mouse model. EVs from BM-MSCs are the most effective in preventing scar formation and heart failure. The mechanism behind their effect has been mapped. We call the product CARMEV 2.0, which is now undergoing final optimization steps, including pig studies, before a phase 1 study proposal.

Expected results and effects

-EVs from hpcMSCs can be reproducibly produced from primary cells -EVs from hpcMSCs are of the order of 150 nm, and express all markers for EVs as well as parts of the MSC markers - Activation of hpcMSCs with TNF-alpha does not increase efficiency - The effect on cardiac remodeling after ischemia -reperfusion injury in mouse model is limited. In contrast: - EVs from BM-MSCs grown according to our GMP-adapted protocol (CARMEV 2.0), are 80 nm in size and effectively prevent heart failure development after myocardial infarction through immunomodulation and extracellular matrix production

Planned approach and implementation

1) Optimizing cultivation protocol: GMP-adaptive, large scale production. 2) Characterization of EVs with FACS 3) Nano Particle Tracking characterization 4) In vitro test: MLR and angiogenesis test 5) Ischemia-reperfusion model in mouse. Ocklusion of LAD (initially 30 min, then 40 min), after which the standard dose (100 billion EVs) is injected intramyocardially. Injection and echo analyzes are double-blinded. 6) Extracellular matrix is analyzed with proteomics. 7) This setup enabled comparison between EVs from hpcMSCs and BM-MSCs, whereby CARMEV 2.0 could be developed.