Combining technologies that have proven highly successful against cancer and in COVID-19 vaccines, researchers at the University of Pennsylvania have shown that they can effectively treat one of the leading causes of heart disease.
For now, success has only been achieved in mice, but the milestone offers hope for millions of people whose heart muscle is damaged by scar tissue.
There is no effective treatment for this fibrosis, which leads to heart disease, the leading cause of death in the United States, said Dr. Jonathan Epstein, a Penn professor of cardiovascular research who helped lead the new work, published Thursday in the journal Science.
In his new research, Epstein reversed fibrosis by reengineering cells, as he did with a successful blood cancer treatment called CAR-T. In this case, however, the treatment was carried out inside the body and not on a laboratory plate.
The team delivered the treatment using mRNA technology, which has been tested over the past year with hundreds of millions of people who received mRNA-based COVID vaccines.
“If it works (in people), it really could have a huge impact,” Epstein said. “Almost all types of heart disease are associated with fibrosis.”
About 50% of heart failure is caused directly by this scar tissue, which prevents the heart from relaxing and pumping effectively. Fibrosis is also involved in the main causes of lung and kidney disease.
In the decade-long CAR-T approach to fighting blood cancers, developed at Penn by study co-author Carl June, the patient’s immune cells are harvested from the body and genetically engineered to identify tumor cells. They are then reinserted so that they can destroy the cancer.
CAR-T, which stands for chimeric antigen receptor T cells, has been enormously expensive because it is customized for each patient. By working within the body, theThe new approach would allow treatment with the same generic approach for all.
“Now it’s scalable. That makes it really more exciting for me,” Epstein said.
Unlike cancer therapy, in which every last cancer cell has to be killed to prevent recurrence, in fibrosis, almost any significant reduction will improve a person’s quality of life, he said.
Although it is still a long way from helping people, the method shows the potential of mRNA technology, far beyond COVID vaccines.
“It’s really cool,” said Dr. Crystal Mackall, a cancer researcher at Stanford University who uses CAR-T to treat cancer and was not involved in this work. “I think we all knew when the COVID vaccine was so successful and so well tolerated in so many people … those of us who are scientists immediately started thinking, ‘Wow, what else can I do with this?'”
In the COVID vaccine, mRNA stimulates cells to produce a protein that is normally foundon the surface of the coronavirus. That way, when the immune system sees the real virus, it will recognize the protein and attack the virus before it can cause serious damage.
In the new application, the mRNA trains the cells to produce a protein that is found on the surface of fibrotic cells, whereby the immune cells will destroy them.
In previous studies, the genetically modified T cells were administered in a way that allowed them to persist for a long time, with the risk of the immune system attacking other fibrotic cells, including those involved in wound healing. By delivering the protein with mRNA, which only remains for a few days, the researchers believe they can avoid this problem.
“The window of potential problems is relatively small,” Epstein said.
This short-term durability is a great advantage, he and others said.
“The idea that you could do this over a period of days is really very exciting,” said Dr. Stanley Riddell, professor and expert in immunology at the Fred Hutchinson Cancer Research Center in Seattle. “It’s a very good state-of-the-art synthetic biology application.”
Still, unexpected problems could arise, and Penn’s team is still a long way from safely treating people with fibrotic heart disease, Epstein said.
Next, they plan to test their approach on larger mammals, before moving on to people, hopefully in about two years. They have yet to determine the most appropriate dose and how many times the treatment needs to be given to be most effective, he said.
The research team has created a company to help advance technology.
One advantage, Epstein said, is that imaging technology can now “see” fibrotic tissue, allowing doctors to assess a patient’s disease and response to therapy. “There are tools that already exist to carry this forward,” he said.
Like many great scientific advances, the idea behind the new treatment approach began with a chance encounter in an elevator.
One of Epstein’s graduate students had wondered aloud about the possibility of using CAR-Ts to treat cardiac fibrosis. A few days later, Epstein ran into June in an elevator and asked the same question.
Graduate students led the effort because “they have the energy to go back and forth between labs,” Epstein said, “and they are smart enough to learn different disciplines.”
The teams had been collaborating for several years when Dr. Drew Weissman, a Penn scientist whose research underlies mRNA vaccines, approached them with a suggestion to administer the treatment via mRNA.
“I walked into Jon’s office and said, ‘We can do this,'” Weissman said.
Weissman, unsurprisingly, is a strong believer in mRNA technology, which is already being tested in other vaccines, to prevent influenza, shingles, and respiratory syncytial virus, as well as cancer. The new study shows it has much broader potential, he said.
Fibrosis is part of many diseases, not just heart disease. Duchenne muscular dystrophy, pulmonary fibrosis, scleroderma and the COVID lung are caused by a hardening of vital tissues, noted Weissman, who is now using mRNA as the basis for an experimental HIV vaccine. People are also experimenting with the use of mRNA to treat autoimmune diseases and administer gene therapies.
“The potential for it is really huge,” Weissman said. “It’s the beginning of the RNA world.”
Contact Karen Weintraub at [email protected]
Patient health and safety coverage in USA TODAY is made possible in part by a grant from the Masimo Foundation for Ethics, Innovation and Competence in Healthcare. The Masimo Foundation does not provide editorial input.
George is Digismak’s reported cum editor with 13 years of experience in Journalism