Researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA say they have engineered a novel experimental drug that may enhance heart repair following a heart attack, with the potential to reduce the incidence of heart failure in patients. The new drug, details of which were published in Cell Reports Medicine, could improve heart function after a heart attack by targeting a protein called ENPP1, which is linked to inflammation and scar tissue formation in the heart.
Cardiovascular disease remains the leading cause of death globally, responsible for approximately one-third of annual fatalities. After a heart attack, the heart’s ability to regenerate is severely limited, causing the organ to form scar tissue to maintain structural integrity. But this rigid scar tissue interferes with the heart’s ability to pump blood, which can lead to heart failure in many patients. Of those who experience heart failure, 50% do not live beyond five years.
“Despite the prevalence of heart attacks, therapeutic options have stagnated over the last few decades,” said senior author Arjun Deb, MD, a professor of medicine, and molecular, cell, and developmental biology at UCLA. “There are currently no medications specifically designed to make the heart heal or repair better after a heart attack.”
The newly developed therapy employs a monoclonal antibody engineered by Deb and colleagues that is designed to inhibit the activity of ENPP1. This protein has been shown to increase following cardiac injury, leading to inflammation and scar tissue formation. In preclinical mouse models, the researchers found that a single dose of their experimental drug significantly improved heart repair in the mice and prevented extensive heart damage. Four weeks after a simulated heart attack, only 5% of treated animals developed severe heart failure, compared to 52% in the control group.
This approach differs from existing treatments that primarily focus on preventing further damage and focuses instead on directly promoting healing of the heart tissue. By enhancing cellular communication within the heart, the therapy benefits various cell types, including heart muscle cells, endothelial cells, and fibroblasts, all of which play important roles in tissue repair.
Initial studies indicate that the antibody not only reduces scar tissue but does so without increasing the risk of heart rupture, which is a common concern after heart attacks. Deb noted, that more research is needed to evaluate the long-term safety of ENPP1 inhibition, as there may be potential adverse effects on bone health or bone calcification.
The team now plans to submit an Investigational New Drug (IND) application to the FDA this winter with a goal of beginning the first human studies early next year. These trials aim to administer the therapy shortly after a heart attack, to help the heart repair itself in the first few days after a heart attack.
Researchers in the Deb lab are also exploring if the experimental drug could be used for treatments in other organs. “The mechanisms of tissue repair are conserved across various organs, so we are investigating how this approach might aid in other forms of tissue injury,” Deb noted. “Based on its effect on heart repair, this could represent a new class of tissue repair-enhancing drugs.”
The implications of successfully developing this therapy are significant. By enhancing the heart’s natural repair mechanisms, the treatment has the potential to reduce mortality rates of patients who might develop heart failure after a heart attack. Current therapies primarily focus on stabilizing the heart post-event, but the ability to actively promote healing may change how healthcare providers approach cardiac care.
