Nearly 18 million people die each year from heart disease, making it the leading cause of death in the world. In the United States alone, the annual economic impact of heart disease exceeds $200 billion, a figure that is expected to rise dramatically. Patients with heart disease experience progressive, significant declines in quality of life marked by reduced activity and higher hospitalization rates. While lifestyle changes and medical treatments are available to slow the progression to end-stage heart failure, there are no lifestyle changes or currently approved medical treatments that have the ability to restore normal heart functioning.
At the Institute for Stem Cell and Regenerative Medicine (ISCRM), researchers in multiple labs are using stem cell technology to pioneer novel approaches to treating heart disease that can potentially cure rather than manage this chronic disease. In 2018, a study led by ISCRM Director Dr. Charles Murry demonstrated that stem cell-derived cardiomyocytes have the potential to regenerate heart tissue in large non-human primates, a major step toward human clinical trials.
These findings represented a major step forward for Murry and his team, a landmark moment after years of working to clear difficult hurdles, including learning how to grow the cardiomyocytes from stem cells, how to ensure the survival of the cells, and how to avoid immunological complications – an undertaking that Murry says remains a work in progress. Now, new evidence suggests the researchers are closer to solving another persistent challenge, known as arrythmia.
“Through the course of our research, we discovered that transplanting stem cell-derived cardiomyocytes into the hearts of large animals caused irregular heartbeats,” says Murry. “The engraftment arrhythmia we saw became one of the biggest impediments as we worked to make heart regeneration ready for the clinic.”
Steady electrical signaling is vital for normal heart functioning. When that signaling is disrupted, the heart can beat too quickly, too slowly, or erratically. Such a side-effect in any treatment could potentially expose a patient to an unacceptable level of risk. Murry and his team have spent years attempting to understand and fix the problem. Electrophysiological studies eventually pointed to a potential culprit.
In a cardiovascular coup d’état known as automaticity, cells that were supposed to be followers appeared to become leaders. The transplanted cardiomyocytes were usurping pace-making duties from the heart itself, preventing it from setting its own rhythm. RNA sequencing of the grafts healing in the host hearts led to a two-part hypothesis: the arrhythmic currents resulted from the presence of ion channels where they should not be, or the absence of channels where they should be, and that gene editing could be used to address the underlying issue, restoring full sovereignty to the heart.
The gene-editing effort, which began in 2018, occurred in six-month cycles. First, combinations of genes that regulate electrical signaling in the heart were altered using gene editing technology. Second, the cardiomyocytes with the edited genes were tested in dishes, then injected into the hearts of large animals. After three years of experiments, a quadruple edit produced the elusive results – heart muscle cells that can beat when stimulated but without causing any sign of arrhythmia.
Silvia Marchiano, PhD, a Postdoctoral Fellow in the Murry Lab performed a majority of the gene editing work, along with fellow lab members Hans Reinecke, PhD and Alessandro Bertero, PhD. Indeed, Marchiano emphasizes the importance that team work played in the research. “We are all part of a huge orchestra,” she says. “Whenever we hit a roadblock, and had to go back and try a different approach, the entire team was supportive. We knew we had to do it together, because it was much more than anyone could ever do alone.”
In a Presidential Symposium lecture titled “Genome Editing to Eliminate Engraftment Arrhythmia during Heart Regeneration,” Murry presented preliminary data from this study on June 21st in a plenary session of the International Society for Stem Cell Research (ISSCR) annual meeting.
Next, the researchers will test to confirm that the changes they make to the cells do not reduce the potential effectiveness of the cell therapy. Ultimately, Murry believes the outlook for heart regeneration is bright. He envisions a future in which a patient who has suffered a heart attack or some other heart-related injury would receive an injection of stem cell-derived cardiomyocytes that would form grafts. These grafts would grow inside the patient, eventually helping to remuscularize the damaged heart, allowing it to pump oxygen and other life-sustaining nutrients throughout the body. “We’re hoping that, if we can remuscularize the wall of the heart, we can prevent patients from a downward spiral of heart failure and help them live full lives with the ability to carry groceries, climb stairs, and play with their grandchildren. That’s the dream I have for this therapy.”
Chuck Murry, MD, PhD, is Senior Vice President and Head of Cardiometabolic Cell Therapy at Sana Biotechnology.
Portions of this research were conducted at Sana Biotechnology