T cells as the antidote for a broken heart

With heartbreak comes a hardening of the heart, oftentimes as an act of self-protection. But in the case of literal injury to heart tissue, the attempt at self-preservation does more harm than good.

During myocardial injury, structure-forming cells called fibroblasts become overly activated, leading to scarring and stiffening of the heart tissue. Currently, there is a need for robust therapies to reverse heart scarring and improve cardiac function of people who have experienced cardiac injury.

Rurik and colleagues at the University of Pennsylvania recently published a paper in Science exploring how depleting fibroblasts can prevent heart scarring in mice.

CAR T cells to the rescue

The investigators sought to use engineered T cells (CAR T cells) to kill disease causing fibroblasts. The researchers made CARs against fibroblast activating protein (FAP), present on the surface of activated fibroblasts, to engineer the T cells to kill the damage causing fibroblasts. 

Classically, CAR T cell therapy consists of isolating T cells from patients, engineering these T cells in the lab to make them better at doing their jobs, and infusing them back into patients.

In vivo CAR T Cell development

Since 1) engineering T cells in the lab is expensive, 2) long term loss of fibroblasts (that are also needed for wound healing) would hinder future wound repair, and 3) persistence of CAR T cells intensifies side effects, the researchers made CARs that are expressed for a short amount of time. Further, these CARs were designed to be made inside the body using the T cell’s own machinery.

mRNA vaccines for cardiac disease 

With the success of COVID-19 mRNA vaccines came the reliability of delivering lipid nanoparticle encapsulated RNA into cells to briefly make protein, after which the RNA is degraded and, consequently, protein production halted. To make a short-lived CARs that deplete fibroblasts, the researchers designed an mRNA encoding the CAR against FAP.

Getting the mRNA into T cells

To engineer T cells, the researchers needed to get the mRNA encoding the CAR into T cells. So, they coated the lipid nanoparticles encapsulating the mRNA with anti-CD5, a molecule highly expressed on T cells. Therefore, upon mRNA injection, the mRNA is ingested by the T cells, leading to the in vivo engineering of T cells that make CARs against FAP (Figure 1). These engineered T cells then kill activated fibroblasts. 

In a mouse model of cardiac disease, the researchers showed improved cardiac function, as measured by an echocardiogram, as well as reduced fibrosis. 

This mRNA based “living drug” CAR T cell therapy sets precedent for future personalized therapies that can acutely target disease causing cells. The ability to engineer T cells in the body would sharply reduce the cost of CAR T cell therapies, increasing healthcare accessibility.

Figure 1: diagram showing how mRNA encoding a CAR against fibroblast activating protein (FAP CAR) is delivered to T cells via a T cell targeted lipid nanoparticle, and how T cells are engineered to transiently produce these CARs in their cytoplasm to be expressed on their cell membrane.

Alia is an Immunology PhD Candidate at Dartmouth studying the processes that keep the immune system from attacking the rest of the body. She is passionate about diversity and inclusion in science. You can find her on twitter @AliaSajani.

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