Engineered Extracellular Vesicle-Based Therapies for Valvular Heart Disease.

Abstract

Valvular heart disease represents a significant burden to the healthcare system, with approximately 5 million cases diagnosed annually in the US. Among these cases,calcific aortic stenosis (CAS) stands out as the most prevalent form of valvular heart disease in the aging population. CAS is characterized by theprogressive calcification of the aortic valve leaflets,leading to valve stiffening. While aortic valve replacement is the standard of care for CAS patients, the long-term durability of prosthetic devices is poor, calling for innovative strategies to halt or reverse disease progression. Here, we explor the potentialuse of novel extracellular vesicle (EV)-based nanocarriers for delivering molecular payloads to the affected valvetissue. This approach aims to reduce inflammation and potentially promote resorption of the calcified tissue. Engineered EVs loaded with the reprogramming myeloid transcriptionfactors, CEBPA and Spi1, known tomediatethe transdifferentiation of committed endothelialcells into macrophages. We evaluated the ability of these engineered EVs to deliver DNA and transcripts encoding CEBPA and Spilinto calcified aortic valve tissue obtainedfrom patients undergoing valve replacement due to aortic stenosis.We also investigated whether these EVs could induce the transdifferentiation of endothelial cells into macrophage-like cells. Engineered EVs loaded with CEBPA + Spi1 were successfully derived from human dermal fibroblasts. Peak EV loading was found to be at 4h after nanotransfection of donor cells. TheseCEBPA + Spi1 loaded EVs effectively transfected aortic valve cells, resulting in thesuccessful induction oftransdifferentiation, both in vitro with endothelial cells and ex vivo withvalvular endothelial cells, leading to the development ofanti-inflammatory macrophage-like cells. Our findings highlight the potential of engineered EVs as a next generation nanocarrier to target aberrant calcifications on diseased heart valves. This development holds promise asa novel therapy for high-risk patientswho may not be suitable candidates for valve replacement surgery. The online version contains supplementary material available at 10.1007/s12195-023-00783-x.