Overcoming Challenges in Cell Therapies for Heart Disease

Pathways to new medicines for heart failure take time, sometimes up to four decades for two now-accepted therapies. As a result, recent efforts to heal scar tissue in infarcted hearts using cells or cell products require more time to create clinical medicines that can minimize the risk of mortality from heart failure following a heart attack.

This message is part of a critical examination of cell-based and cell product-based treatments for heart failure. The review covers 20 years of completed and ongoing clinical trials. While none have received medical approval, they have proven to be safe, with some even showing therapeutic effects.

More crucially, the reviewers point out that it took nearly four decades to optimize two existing medicines for reducing mortality in heart failure: implanted cardioverter-defibrillators and guideline-directed medical therapy.

“The history of the development of life-saving medical therapies for heart failure serves as an important lesson that we should remain hopeful of the promise of cell therapy in heart failure,” Jianyi “Jay” Zhang, M.D., Ph.D., and colleagues write in the review, “Trials and tribulations of cell therapy for heart failure: an update on ongoing trials,” published in Nature Reviews Cardiology. Zhang is professor and chair of the University of Alabama at Birmingham Department of Biomedical Engineering.

Heart failure accounts for 13% of deaths worldwide. Half of all heart failure patients die within 5 years. The most prevalent cause of heart failure is coronary artery obstruction, which results in the loss of cardiomyocytes, or heart muscle cells. When muscle tissue is replaced by dense scar tissue with limited blood circulation, the infarcted heart loses contractile strength, resulting in cardiac enlargement, progressive loss of pumping function, an increased risk of ventricular arrhythmias, and clinical end-stage heart failure.

The journey over the last two decades has been fraught with challenges. The three sections of the Nature Reviews Cardiology publication detail the voyage.

The first section discusses the gradual development, hurdles, setbacks, and skepticism surrounding two modern heart failure therapies: implanted cardioverter-defibrillators and guideline-directed medical therapy. The following two sections – and the review’s main focus – survey 13 completed clinical trials published in the last 12 years, as well as 10 very recently initiated and ongoing clinical trials based on lessons learned from the previous 20 years of research, to assess the safety and efficacy of cell- and cell product-based therapy approaches.

While several randomized, double-blind, multicenter phase II or III trials published in the last 20 years support the idea that even a single dose of cell products has beneficial effects in patients with heart failure on optimal medical therapy, Zhang says the current trials are taking new directions.

This includes:
New cell types include pluripotent stem cell-derived cardiomyocytes/spheroids and umbilical cord-derived mesenchymal stem cells.
Using repeated intravenous injections as a noninvasive cell delivery method
Engineered epicardial cardiomyocyte patches are an example of new cell products.
Novel cell-free products include secretomes that are abundant in extracellular vesicles or exosomes.

The results of these trials will continue to define and refine our understanding of cell and cell product therapy as a novel addition in the treatment of patients with heart failure.”

Jianyi “Jay” Zhang, Department of Biomedical Engineering, University of Alabama at Birmingham

The study acknowledges scientific criticism during the slow but steady advancement and evolution of cell therapy. Some have questioned the use of public funds to support cell therapy research for heart failure treatment, citing poorly designed or underpowered clinical trials and very modest improvements in cardiac function in preclinical studies that are not always replicated in large-scale clinical trials.

“These criticisms must be addressed in future trials that are adequately powered and rigorously designed to ensure continued progress of the field,” Zhang said. “Critique is an essential part of science, and the basis for growth, innovation and evolution -; this is no less true for the field of cell therapy.”

Yet Zhang is confident that current research will yield clinical translation. “In the past 20 years, cell therapy has emerged and evolved as a promising avenue for cardiac repair and regeneration,” he said. “Cell therapy has encountered substantial barriers in both preclinical studies and clinical trials, but the field continues to progress and evolve through lessons learned from such research.”

For more information: Zhang, J. J., et al. (2024) Trials and tribulations of cell therapy for heart failure: an update on ongoing trials. Nature Reviews Cardiology. doi.org/10.1038/s41569-024-01098-8.