mRNA against heart failure
Researchers from the University of Pennsylvania's Perelman School of Medicine have demonstrated a new method of immunotherapy using an mRNA-based drug that reprograms a patient's T cells to attack hyperactive heart fibroblasts.
Heart failure, as a rule, is partially associated with impaired functioning of fibroblasts, which respond to heart damage and inflammation by chronic excessive synthesis of intercellular matrix components, which leads to fibrosis and weakening of the myocardium. In experiments on mouse models of heart failure, a decrease in the number of fibroblasts due to reprogrammed T-lymphocytes led to tissue repair.
The new technique is based on CAR T-therapy technology. In the classical version, it requires the collection of the patient's T cells and their genetic reprogramming to recognize markers on specific types of cells in the body. These altered T cells are then injected into the patient to attack a specific type of cell. The CAR T-therapy method was created by researchers at the University of Pennsylvania and the Children's Hospital of Philadelphia. The U.S. Food and Drug Administration in 2017 approved it for the treatment of leukemia and lymphoma – tumors that arise from B-lymphocytes.
The authors suggested that CAR T-therapy technology could be used to treat other diseases, including heart fibrosis and heart failure. To do this, it was necessary to modify it, since in a healthy body fibroblasts are necessary, especially for wound healing, and CAR T cells targeting fibroblasts can persist in the body for months or even years, suppressing their population during all this time.
In the new study, the group developed a technique for a temporary and controlled, and from a methodological point of view, a much simpler type of T-cell therapy. For this purpose, matrix RNA (mRNA) was used, which encodes a chimeric antigen receptor (CAR) aimed at hyperactive fibroblasts. This mRNA was placed in lipid nanoparticles, which themselves are covered with molecules contained in T cells. This technology is already being used in mRNA-based COVID-19 vaccines.
The encapsulated mRNAs injected into mice are absorbed by T lymphocytes and act in the nucleus as a template for the production of a receptor protein targeting fibroblasts. Thus, immune cells are reprogrammed to attack fibroblasts, but the effect is temporary, since mRNAs do not integrate into DNA and survive in T-lymphocytes for only a few days, after which the cells return to normal and no longer attack fibroblasts.
The researchers found that, despite this short-lived activity, a single injection of mRNA to mouse models of heart failure led to the reprogramming of most of the T-lymphocyte population, which led to a significant reduction in cardiac fibrosis in animals and the restoration of normal heart size and function without signs of continued T-cell activity against fibroblasts a week after treatment.
The researchers will continue to test the mRNA technology of CAR T therapy in the hope of moving to clinical trials soon.
Article by J.G.Rurik et al. CAR T cells produced in vivo to treat cardiac injury is published in the journal Science.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru According to the University of Pennsylvania: Vaccine-like mRNA injection can be used to make CAR T cells in the body.