Reactivating a Naturally Occurring Gene Promotes Heart Repair and Regeneration

A naturally occurring gene called Cyclin A2 (CCNA2), which turns off after birth in humans, can actually make new, functioning heart cells and help the heart repair itself from injury including a heart attack or heart failure when the gene is turned back on. These are the breakthrough results from a Mount Sinai study published November 3, in Nature Portfolio Journals Regenerative Medicine. This first-time discovery made by Hina Chaudhry, MD, Director of Cardiovascular Regenerative Medicine at the Icahn School of Medicine at Mount Sinai, and her team could lead to new techniques to repair damaged hearts, as an alternative to heart transplants or implanted cardiac devices.

This groundbreaking work builds on Dr. Chaudhry's landmark 2014 study in Science Translational Medicine, in which her team became the first in the world to regenerate the heart of a large mammal (pig) after a heart attack by reactivating CCNA2. These hearts closely mimic the heart of humans. That work demonstrated that the approach could heal the most clinically relevant heart model. Now, the new study provides the translational bridge, proving that a human-compatible viral vector can safely and effectively trigger cell division in adult human heart cells.

Heart disease is the leading cause of death worldwide, yet adult human heart muscle cells stop dividing after birth. Our work was the first to show that we can regenerate the porcine heart after injury, and now we've advanced the field by demonstrating that even middle-aged adult human heart cells-long believed incapable of division-can be coaxed back into making new, functional cells. This shifts the paradigm from managing symptoms to actually repairing the human heart."

Dr. Hina Chaudhry, MD, Director of Cardiovascular Regenerative Medicine at the Icahn School of Medicine at Mount Sinai

When someone has a heart attack or heart failure, heart muscle cells are lost and the heart cannot replace them. There is no current way to grow new heart muscle cells after damage. Dr. Chaudhry and her team wanted to know if they could reawaken the heart's ability to regenerate itself by using a naturally occurring pathway that enables cardiomyocyte (heart muscle) cell division in utero. They focused on CCNA2-a gene that is normally silenced after birth-and turned it back on in adults to see if this would help grow new heart cells and help the heart heal.

The research team built a replication-deficient human-compatible virus that carries the CCNA2 gene and delivered it to heart muscle cells. They tested it directly in living adult human heart cells in culture from healthy donor hearts. Researchers used time-lapse imaging to analyze the heart cells with CCNA2 and saw these cells divide successfully, while still keeping their normal structure and function.

More specifically, researchers looked at three healthy hearts from donors who were 21, 41, and 55-years-old. Cyclin A2 therapy triggered these adult human heart cells to divide in the 41- and 55-year-old hearts. Conversely, cells from hearts belonging to a 21-year-old showed no change when given the CCNA2 therapy. This latter finding aligns with previous studies that show younger hearts do have regenerative potential and that their cells are capable of dividing without the stimulus provided by CCNA2.

Importantly, daughter cells-cells resulting from cell division-retained their structural proteins and normal calcium activity, indicating they remain functional. Further analysis showed that CCNA2 helps heart cells briefly "turn back the clock," by reactivating certain growth genes so they can divide and repair the heart. Notably, this process does not make the cells immature or cause the harmful thickening of heart tissue seen in disease.

"This is the culmination of nearly two decades of work," Dr. Chaudhry said. "We pioneered the concept that the heart could be regenerated by reawakening dormant cell division genes, and now we've brought that vision one step closer to patients. Our goal is to deliver a therapy that allows the heart to heal itself after a heart attack or in heart failure-reducing the need for transplants or mechanical devices."

The next step will be to seek FDA approval to begin clinical trials of CCNA2 therapy in patients with heart disease.

This study was supported by the National Institutes of Health and the New York Stem Cell Board.