Millions of people die every year from fibrosis, a build-up of scar tissue in the liver, heart, and other organs. Scars are key to healing, but sometimes “the scar becomes a problem instead of the solution,” says Scott Friedman, a liver disease specialist at the Icahn School of Medicine at Mount Sinai.
Now, by blending technologies behind cancer immunotherapy and COVID-19 vaccines, scientists have eased fibrotic scarring in the hearts of mice. Like all animal work, the research has a way to go before reaching humans. But experts are excited by the approach because it tackles a major medical need in a way that appears promising for widespread use. “We’re bereft of therapies” for fibrosis, says Friedman, who was not involved with the work. “This is a totally new angle.”
A chance encounter in an elevator a few years ago helped spark the new strategy. Jonathan Epstein, a cardiologist and chief scientific officer at the University of Pennsylvania’s Perelman School of Medicine, ran into oncologist Carl June, who, more than 10 years ago, had pioneered a personalized immune cancer treatment. That approach uses engineered T cells, the sentries of the immune system, to selectively target and destroy cancer cells. Called CAR-T cell therapy, it has become a powerful blood cancer treatment.
In 2019, Epstein and his colleagues described success in applying the approach to fibrosis, with the goal of targeting connective tissue cells called fibroblasts that lay down excess scar tissue in the heart. Just as cancer experts had been doing in people, they removed blood from mice, isolated the T cells, and engineered them to target a subset of hyperactive fibroblast cells with a specific molecule on their surface, called fibroblast activated protein (FAP). In rodents with cardiac fibrosis induced by high blood pressure, the reinfused T cells restored the function of the organ to near normal, they reported that year in Nature.
Epstein knew, however, that this was only the beginning. In cancer treatment, CAR-T therapy is personalized for every patient and crafted outside the body—making it laborious, expensive, and limited to major medical centers. The modified cells can also linger in the body for years—a boon to keeping cancer at bay, but not ideal for fibroblasts, which the body often needs and which it’s not a good idea to target long-term.
So Epstein’s team weaved in another technology that would modify T cells inside the body. That technology is the same one used by many COVID-19 vaccines: lipid nanoparticles that carry a modified messenger RNA (mRNA). In Epstein’s design, the mRNA contains the blueprint for T cells to target FAP. The team also added a molecule to the outside of the nanoparticles that sticks to a receptor on the surface of T cells.
When the nanoparticles are injected, T cells should take them up. Just like T cells engineered outside the body in traditional CAR-T therapy, they use the mRNA instructions to become primed to target and kill the fibroblast cells displaying FAP. But unlike the traditional version of CAR-T therapy, here the T cells are only “engineered” temporarily; once the mRNA degrades—in a matter of days—the cells revert to normal.
With graduate student Joel Rurik, Epstein tested the strategy in the same mouse model of high blood pressure used earlier. Before any treatment, the mice were left alone for 1 week to begin developing fibrosis in their heart. Then, they received a single injection of either mRNA-containing nanoparticles or saline as a placebo.
Two weeks later—a time when the hearts of sick animals would look markedly different than healthy ones—the scientists examined the organs. The hearts of the treated mice were not completely normal, but they were markedly improved, with a pumping capacity that nearly matched control mice. On average, scar tissue made up 2.5% of the heart ventricles in treated rodents, compared with roughly 1% for normal animals and 4% in ailing ones, the team reports today in Science.
“This is terrific because of the ingenuity of the strategy,” says Guillermo Torre-Amione, a cardiologist and immunologist, and president of the Tecnológico de Monterrey Health System in Mexico. “It’s a cell that goes and targets the activated fibroblasts, [and] it kills the fibroblasts selectively.”
A key question for humans is safety. “In the mice studied so far, there seem to be no side effects,” says Nadia Rosenthal, a molecular geneticist and scientific director at the Jackson Laboratory. mRNA’s short life span and its inability to incorporate into a cell’s DNA make her hopeful.
“It’s the transient nature … that is so critical to the safety part of this story,” Rosenthal says. “Any disease that involves fibrosis could conceivably benefit from this approach.”