mRNA

Heart failure is the leading cause of death in the Western world, causing more than 300,000 deaths per year. Heart failure is also a source of significant economic burden, costing the American healthcare system more than 30 billion dollars in 2012.[i] Cardiac fibrosis is central to the pathology of heart failure. Cardiac fibroblasts are activated in response to injuries. However, when activated fibroblasts fail to quiesce and continue secreting extracellular matrix, cardiac fibrosis occurs, leading to scarring of heart tissues. Ultimately, cardiac fibrosis can lead to fatal heart failure. Fibrotic diseases, including lung and cardiac fibrosis, cause more than 800,000 deaths worldwide per year.[ii]

Researchers from the laboratory of Dr. Jonathan Epstein in the University of Pennsylvania recently showed that mRNA therapeutics can be used to address cardiac fibrosis.[iii] The researchers delivered a modified mRNA coated with T-cell targeting lipid nanoparticles. The mRNA encodes for a chimeric antigen receptor against FAP, a specific protein expressed by activated fibroblasts. This allows for the generation of transient chimeric antigen receptor T (CAR-T) cells that recognize fibrotic cardiac cells.

Successfully delivered, the mRNA was able to reprogram T cells to specifically recognize and eliminate activated fibroblasts. In a mouse model of heart failure, the engineered CAR T cells were able to resolve cardiac fibrosis, restructuring the heart and improving heart function after injury. Unlike ex vivo CAR-T cells generation, this method allowed the generation of CAR T cells entirely in the human body. In addition, these engineered CAR T cells are transient, therefore not compromising the heart’s ability to resolve future injuries through fibroblast activation.

With the recent advances of the COVID-19 vaccines, the use of mRNA therapeutics in other diseases is gaining traction. The possibility of eliminating the disease burden of cardiac fibrosis using mRNA therapeutics is extremely attractive, as it has the potential to reverse cardiac fibrosis and restore heart function. This presents a significant addition to existing antifibrotic agents that only limit or slow down fibrosis progression. This first proof-of-concept study opens a new avenue to optimize the strategy of combining mRNA therapeutics and CAR-T technology to address cardiac fibrosis and fibrotic diseases in general.

References:

[i] Virani, S. S. et al. (2021) Circulation 143: e254–e743

[ii] Hinderer, S. and Schenke-Layland, K. (2019) Advanced Drug Delivery Reviews 146: 77-82

[iii] Rurik, J. et al. (2022) Science 375.6576: 91-96

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