Extracellular vesicles (CARMEV) for prevention of heart failure
Lead: Karl-Henrik Grinnemo, professor at Dept of surgical sciences, Uppsala University. Consultant Cardiothoracic Surgery, Uppsala University Hospital
Involved partners: AstraZeneca, IsletOne and Uppsala University
To prevent development of heart failure after a myocardial infarction by injection of extracellular vesicles from bone marrow-derived mesenchymal stromal cells (BM-MSCs).
Examples of tasks and actions:
The first work package (WP) includes development of strategies for production of pure EVs from BM-MSCs. We will use our patented expansion protocol and harvest EVs at each passage using serum-free media. The EVs will be tested for their capacity to stimulate angiogenesis (vessel formation) and convert the immune response from pro-inflammatory to more immune modulating in mixed lymphocyte reaction test. The final test of the EVs will be in a blinded in vivo study, where EVs from BM-MSCs will be tested against particles from control medium in an infarction model in mice. The EVs or controls will be injected at the time of the ischemia-reperfusion injury and the effect omg myocardial function as well as left ventricle dimensions will be followed for 4 weeks with echocardiography. This study is ongoing.
Interview with project leader
Hi Karl-Henrik Grinnemo!
What is the need your project addresses?
Survival after myocardial infarctions and subsequent heart failure has not improved over the last decade despite the use of modern pharmacological and interventional. The most important reason is that guideline-directed treatment of today do not affect the reperfusion injury after coronary artery intervention (PCI). Restored blood flow (reperfusion) after PCI causes production of reactive oxygen species (ROS) from the affected myocardium, initiating a vicious cycle of inflammation, obstruction of capillaries, cardiomyocyte deaths ending up with scar formation and heart failure.
What is your approach to meet the need?
We have recently demonstrated that cardiac mesenchymal stromal cells from the developing heart (termed human prenatal cardiac MSCs, hpcMSCs) demonstrate cardiac progenitor characteristics, are immunomodulatory, inhibit apoptosis, stimulate angiogenesis and improve myocardial function back to normal after a major myocardial infarction in rats. Importantly, the effects are mainly mediated by the extracellular vesicles (EVs). Cells with similar characteristics can also be generated from Bone Marrow MSCs (BM-MSCs) when cultured according to a protocol developed in my lab. Based on the findings, we propose the following process development concept: production of factors (paracrine factors) secreted from iBM-MSCs (cell-lines) for prevention of heart failure after a myocardial infarction- CARdiac Mesenchymal Extracellular Vesicles (CARMEV). The partners of this project are: Uppsala University, Akademiska Hospital, AstraZeneca and IsletOne AB.
How will this improve Sweden’s capabilities within ATMPs?
The use of EVs from BM-MSCs is a new concept, where all steps, including expansion of BM-MSCs as well as EV-generation are patent protected in the Swedish company IsletOne AB. If the pre-clinical testing is successful, the next step is up-scaling and testing in large animal studies before generating a biological drug. AZ is one of the partners, and they have the right of first refusal. With this EV-based product, Swedish Big Pharma has the chance of positioning a new drug (ATMP) for prevention of heart failure after a myocardial infarction. EVs are easy to store and distribute, which makes the product suitable for wide-bread distribution all PCI-labs all the world.
For more information on this Project please Contact Karl-Henrik Grinnemo