Chimeric antigen receptors applied to T cells, known as CAR-T therapies, are expensive. Isolating a patient's T cells, culturing them, engineering them, and then returning them to the body is an undertaking, particularly when it must be carried out with the very high level of reliability and quality control required by regulators. CAR-T therapies do well in attacking many types of cancer, but can have side-effects due to the lasting presence of engineered immune cells that have become too zealous. Few chimeric antigens are completely specific for cancer, and other cells will be destroyed as well. The approach noted here is an interesting one: temporarily turn a patient's circulating T cells into CAR-T cells by delivering an mRNA gene therapy. This can minimize off-target effects, while still creating a period of days in which the immune system targets undesirable cell types for destruction.
Researchers have demonstrated a new approach with an mRNA preparation that reprograms T cells to attack heart fibroblast cells. Heart failure is often driven in part by these fibroblast cells, which respond to heart injury and inflammation by chronically overproducing fibrous material that stiffens the heart muscle, impairing heart function - a condition called fibrosis. In experiments in mice that model heart failure, the reduction in cardiac fibroblasts caused by the reprogrammed T cells led to a dramatic reversal of fibrosis.
The new technique is based on chimeric antigen receptor (CAR) T cell technology, which, until now, has required the harvesting of a patient's T cells and their genetic reprogramming in the lab to recognize markers on specific cell types in the body. These specially targeted T cells can then be multiplied using cell culture techniques and re-infused into the patient to attack a specific cell type. However, this standard CAR T cell strategy would be problematic when directed against heart failure or other fibrotic diseases in humans. Fibroblasts have a normal and important function in the body, especially in wound healing. CAR T cells that are reprogrammed genetically to attack fibroblasts could survive in the body for months or even years, suppressing the fibroblast population and impairing wound healing for all that time.
Therefore, in the new study, researchers devised a technique for a more temporary and controllable, and procedurally much simpler, type of CAR T cell therapy. They designed mRNA that encodes a T-cell receptor targeting activated fibroblasts and encapsulated the mRNA within tiny, bubble-like lipid nanoparticles (LNPs) that are themselves covered in molecules that home in on T cells. Injected into mice, the encapsulated mRNA molecules are taken up by T cells and act as templates for the production of the fibroblast-targeting receptor, effectively reprogramming the T cells to attack activated fibroblasts. This reprogramming is very temporary, however. The mRNAs are not integrated into T-cell DNA and survive within T cells for only a few days - after which the T cells revert to normal and no longer target fibroblasts.