Heart failure is often driven in part by fibroblast cells. These cells respond to heart injury and inflammation by chronically overproducing fibrous material that stiffens the heart muscle, thus impairing heart function, a condition called fibrosis.

Clinical trials using antifibrotic therapeutics have only demonstrated a modest effect. To address this clinical challenge, researchers at the University of Pennsylvania (UPenn) have demonstrated the use of CAR T cells to specifically eliminate activated fibroblasts as a therapy for heart failure. (Science, January 6, 2022, Vol. 375:6576, pp. 91-96)

CAR T cells target T cells and can be multiplied using cell culture techniques and reinfused into a patient to attack a specific cell type. The first CAR T-cell therapy was developed by researchers from UPenn and the Children's Hospital of Philadelphia. It was approved by the U.S. Food and Drug Administration in 2017 to treat certain leukemias, and later, it was approved for lymphoma.

Although CAR T-cell technology is currently used primarily to treat cancers, with dramatic results in many otherwise hopeless cases, its developers have long envisioned harnessing the approach for other diseases. Dr. Jonathan Epstein, chief scientific officer for Penn Medicine and executive vice dean and the William Wikoff Smith professor of cardiovascular research of the Perelman School of Medicine at UPenn, and colleagues showed in a 2019 study that the standard CAR T-cell approach can be used to attack overactive cardiac fibroblasts and restore heart function in a mouse model of heart failure.

In the current study, the authors generated modified nucleoside-containing mRNA, encoding a CAR designed against fibroblast activation protein (FAP) (a marker of activated fibroblasts) and packaging it in CD5-targeted T cell-targeted lipid nanoparticles (LNPs) (referred to as targeting antibody/LNP-mRNA cargo or CD5/LNP-FAPCAR).

These LNP-generated CAR T cells were able to effectively kill FAP-expressing target cells in vitro with 89% to 93% efficiency. Mice were injured to allow fibrosis to be established before injecting CD5/LNP-FAPCAR. Two days after LNP injection, authors found a consistent population of FAPCAR+ T cells (17.5%-24.7%) exclusively in mice that received CD5/LNP-FAPCAR.

The researchers also reported marked functional improvements in injured mice treated with in vivo-produced transient FAPCAR T cells. Injured mice treated with CD5/LNP-FAPCAR exhibited normalized left ventricular and end-diastolic volumes. Though body weight did not show statistically significant differences after CD5/LNP-FAPCAR injection, the trend in improvement compared with control mice was noted.

Injections of the mRNA in mice that modeled heart failure successfully reprogrammed a large population of mouse T cells, causing a major reduction of heart fibrosis and a restoration of mostly normal heart size and function with no evidence of continued antifibroblast T-cell activity one week after treatment.

The researchers are continuing to test this mRNA-based transient CAR T-cell technology, with the hope of eventually starting clinical trials.

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