Physician-researchers at the University of Miami Miller School of Medicine and collaborators at Stanford University, the University of Texas and the University of Louisville are leading a $14 million Department of Defense (DOD) grant to study why some patients with non-ischemic heart failure respond to mesenchymal stem cell therapies and others may not. Specifically, the scientists want to identify the genetic variations that may drive these distinctions.
This research, called POSIEDON DCM-2, follows up on an earlier study by Miller School investigators, which showed that genetics may strongly influence how patients with non-ischemic heart muscle dysfunction respond to mesenchymal stem cell (MSC) therapies. Non-ischemic refers to damage caused by conditions other than coronary artery disease.
“The people who did not have any genetic defects had a huge response to the cell therapy,” said Joshua Hare, M.D., principal investigator on the DOD study and director of the Miller School’s Interdisciplinary Stem Cell Institute. “The group with genetic defects were clearly not responding.”
Found in bone marrow, fat and umbilical cords, MSCs are adult stem cells that can help regenerate a narrow range of human tissues, including heart muscle. Researchers have been studying MSCs as a potential heart failure treatment for years, with mixed results.
The patients in both the previous study and the POSIEDON trial suffer from non-ischemic heart failure. In other words, their disease was caused by a virus, an autoimmune response or other issue – not loss of blood flow to the heart. Non-ischemic patients generally respond better to MSC therapies than their ischemic counterparts, but scientists and clinicians have needed more data to understand why only some non-ischemic patients benefit.
“The fact that these patients fairly sharply separate into non-responders and responders leads to a question,” said Robert Myerburg, M.D., professor of medicine and co-investigator on the upcoming study. “Is there something about one group or the other that characterizes them as being more susceptible to the disease or less susceptible or less amenable to the therapy? Our initial study suggested that those with an apparent genetic basis for non-ischemic heart muscle dysfunction did not respond to MSC therapy, while those with other causes did respond.”
While the earlier study produced intriguing results, the researchers note that it did not have a control group and, with only 34 patients, was quite small. Dr. Hare and Dr. Myerburg felt the research produced a strong signal, but they would need to conduct a more rigorous trial to determine if those initial results were accurate and offer the potential to advance clinical practice.
POSIEDON DCM-2 will be a 136-patient, double-blind prospective study – the gold standard for clinical trials. The investigators believe the larger study will give them more information to delineate the impact of variants of uncertain significance – changes in the genetic code that may or may not influence a patient’s response to treatment. The larger study will also help determine if the cell therapy is actually working in non-responders, just not as well.
The researchers hope the new study will validate their previous work and ultimately benefit non-ischemic heart failure patients. Understanding the genetic basis for their disease could lead to better diagnostics to determine who will respond to MSC therapy, ensuring patients receive the most effective, personalized treatments for their condition.
“Patients who have a genetic basis for the disease are far less likely, from the data we have so far, to respond to cell therapy,” said Dr. Myerburg. “That’s our hypothesis, and the larger study will give us more information to determine if it’s accurate. If it is, that could change how we provide mesenchymal stem cell therapy for this class of patients.”