Oftentimes, though, these innovations are first used in relatively rare diseases. What about the most common ones, like the leading cause of death worldwide—heart disease?
Multiple research teams at Penn Medicine are continuing to advance the science to develop new treatments for heart disease that could work with just one shot—three different ways that a single injection could someday heal the heart.
Editing genes to reduce cholesterol
Penn Medicine cardiologist Kiran Musunuru, MD, PhD, MPH, ML, director of the Genetic and Epigenetic Origins of Disease Program in Penn’s Perelman School of Medicine, leads innovative research that uses therapeutic gene editing to combat cardiovascular disease.
Musunuru discovered a gene that regulates LDL cholesterol, which inspired the development of multiple drugs targeting a protein related to that gene pathway. In his lab, he has since developed processes to use CRISPR gene editing technology to modify genes in the liver to permanently reduce cholesterol levels and therefore provide protection against heart attack and stroke. The approach, a one-time injection like a vaccine that might prevent heart disease if it is successful, is now in clinical trials in the U.K. and New Zealand and has been approved by the U.S. Food and Drug Administration to begin trials in the U.S. soon. The biotechnology company running the trials reported at the American Heart Association meeting in November 2023 that among the trial’s earliest participants, the injection reduced LDL in the blood by up to 55 percent.
An injection of mRNA that targets the heart muscle
Nobel Prizewinning scientist Drew Weissman, MD, PhD, the Roberts Family Professor in Vaccine Research and director of the Penn Institute for RNA Innovation, is working on multiple uses of mRNA to treat or prevent heart disease. Unlike gene editing, messenger RNA (mRNA) is a set of instructions for the body to make a protein. Normally in the body, mRNA works like a recipe to use the code within our DNA to build a protein needed to carry out our cells’ functions. An mRNA vaccine or therapy can deliver a recipe for our cells to build any type of protein without altering our original DNA.
Working with Vlad Muzykantov, MD, PhD, the Founders Professor in Nanoparticle Research, Weissman’s lab has developed a way to target an mRNA injection to act specifically in heart cells. “Drugs for heart disease aren’t specific for the heart,” Weissman said. “And when you’re trying to treat a myocardial infarction or cardiomyopathy or other genetic deficiencies in the heart, it’s very difficult, because you can’t deliver to the heart.” While it is not yet ready for human trials, the new mRNA technique could potentially repair the heart or increase blood flow to the heart, noninvasively, after a heart attack or to correct a genetic deficiency in the heart.
Reprogramming immune cells to heal the heart
Penn Medicine researchers are also combining two of their biggest innovations—CAR T cell therapy and mRNA therapeutics—as an approach to treat fibrosis, an impairment of heart function which is often a factor in heart failure. Fibrosis occurs when fibroblast cells react to heart injury and inflammation by chronically overproducing fibrous material that stiffens the heart muscle.
Last year, a Penn research team that included Weissman published a study in Science, demonstrating their new approach that used mRNA to reprogram T cells—a powerful type of immune cell—to attack heart fibroblast cells. In experiments in mice that modeled heart failure, the reduction in cardiac fibroblasts caused by the reprogrammed T cells led to a dramatic reversal of fibrosis.
“Fibrosis underlies many serious disorders, including heart failure, liver disease, and kidney failure, and this technology could turn out to be a scalable and affordable way to address an enormous medical burden,” said senior author Jonathan A. Epstein, MD, chief scientific officer for Penn Medicine and executive vice dean and the William Wikoff Smith Professor of Cardiovascular Research in the Perelman School of Medicine.
An important aspect of this new technique is that it is a localized and temporary reprogramming of T cells in the body. In CAR T cell therapies that treat cancer, a patient’s T cells are extracted from the body and reprogrammed to attack cancerous cells, and then re-infused. The engineered T cells may reproduce and persist in the body for years, or even a decade or more in patients with long-term remissions.
But because fibroblasts have an important role in wound healing, Epstein and colleagues came up with their method to modify T cells only temporarily. The mRNA they injected acted like a temporary change in the software code when it reached the T cells—it gave instructions for these cells to make a protein on their cell surface that targets fibroblasts. But unlike traditional CAR T cell therapies, this method did not rewire the hardware, or change the DNA, of the T cells. The mRNA molecules survive within T cells for only a few days—after which the T cells revert to normal and no longer target fibroblasts.