Some of the biggest innovations in modern medicine started at Penn Medicine, including the first gene therapy, the first cellular therapy (CAR T cell therapy) that reprograms the immune system to fight cancer, and the technology behind the first mRNA vaccines (work that was awarded the Nobel Prize this fall).
Oftentimes, though, these innovations are first used in relatively rare diseases. What about the most common ones, like 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.
Editing genes to reduce cholesterol
Penn Medicine cardiologist Kiran Musunuru, MD, PhD, leads innovative research that uses gene editing to combat cardiovascular disease.
Musunuru discovered a gene that regulates LDL cholesterol, which led to multiple drugs targeting a protein related to that gene. 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. 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 in November 2023 that among the earliest participants, the injection reduced LDL in the blood by up to 55%.
An injection of mRNA that targets the heart muscle
Normally in the body, messenger RNA (mRNA) works like a recipe to use the code within our DNA to build a protein needed to carry out our cells’ functions. Nobel Prize-winning scientist Drew Weissman, MD, PhD, the director of the Penn Institute for RNA Innovation, is studying potential mRNA vaccines and therapies that deliver a recipe for our cells to build any type of protein without altering our original DNA.
Working with nanoparticle researcher Vlad Muzykantov, MD, PhD, Weissman’s lab has developed a way to target an mRNA injection to act specifically in heart cells. 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.
Reprogramming immune cells to heal the heart
Penn Medicine researchers are combining two of their biggest innovations—CAR T cell therapy and mRNA therapeutics—to treat fibrosis, a stiffening of muscle which is often a factor in heart failure, liver disease, and kidney failure.
In 2022, 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, the type that stiffen in fibrosis. In experiments in mice that modeled heart failure, they saw a dramatic reversal of fibrosis.
“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, interim dean of Penn’s Perelman School of Medicine.
This is a local and temporary reprogramming of T cells in the body to only attack fibroblast cells for a few days, which is important because fibroblasts also play an important role in wound healing. By contrast, the type of engineered cancer-fighting T cells in traditional CAR T cell therapies may persist in the body for years.
The researchers are continuing to test this mRNA-based, transient CAR T cell technology, with the hope of eventually starting clinical trials.
