Using cell-based cardiac regenerative medicine to combat heart disease
Heart disease has a staggering death toll of more than 600,000 people a year. Current treatments for severe forms of cardiac dysfunction is typically organ transplantation, but the demand for donor hearts far exceeds availability, with only about 2,000 patients receiving a heart transplant per year. Dr. Charles Murry, Professor of Pathology, Bioengineering, and Cardiology/Medicine, Interim Director at the Institute for Stem Cell and Regenerative Medicine, and Co-Director at the Center for Cardiovascular Biology at University of Washington, is developing novel technologies that enable the use of cell transplantation as a regenerative therapeutic alternative to combat severe cardiac deterioration. He uses innovative tissue engineering and cell reprogramming technologies to develop platforms that enable the characterization of novel therapeutic agents; cell-based restoration of heart function has moved from an implausible idea to a tangible and promising approach, which has the potential to impact millions of people suffering from heart disease.
A key factor for the success of this innovative therapy is finding a suitable source of human cardiac muscle, which is difficult. Though many cell types have been examined, only pluripotent stem cells are shown to be effective at generating these cells at therapeutically relevant levels. Although pluripotent stem cells have the capacity to become any cell type in the body during the earliest stages of development, they become restricted (in their potential to become other cell types) and functionally specialized when they mature. Some organs, such as the liver, retain a capacity to replenish lost cells and repair itself. The heart, however, cannot. Dr. Murry has been at the forefront in the characterization of potential sources of suitable cells, as well as the development of efficient methods to generate human cardiac muscle cells. Over the last 15 years, he has used these cells to gain significant insight into fundamental molecular mechanisms that regulate human heart development.
Dr. Murry’s team comprises more than 30 scientists, academic personnel, trainees, and staff who specialize in pathology, bioengineering, medicine, and cardiology. They collaborate with numerous research labs and institutions. Together, they are taking a broad approach to tackling cardiac disease. This includes exploring novel molecular mechanisms that regulate human heart development, engineering cardiac tissue, modeling disease in cultured cells, and developing stem cell-based approaches to treat heart disease. Dr. Murry and his team have made lab-engineered cardiac tissue, using it to assess mechanical function. They have pioneered cell transplantation studies in small animal models that have provided strong proof of concept data regarding the potential therapeutic use of these human cardiac muscle cells. Recently, they moved this novel research closer towards clinical applications and have initiated studies in non-human primates. Dr. Murry and his team’s advanced cell transplantation studies will lead to an expected phase I clinical trial in 2019.
Current research includes:
- Developing novel cell-based regenerative therapies - During a heart attack, approximately 1 billion heart muscle cells are lost. Dr. Murry and his team would like to develop a regenerative therapy that will enable the functional replacement of the lost heart muscle cells. Their research identified human pluripotent stem cells as the best source of therapeutically-relevant human cardiac muscle. After successful studies in rodent models of heart disease, they are currently assessing therapeutic potential in the pre-clinical gold standard non-human primate model. Human clinical trials are targeted to begin in 2019.
- Modeling disease with cells in culture - Although it is well established that most cases of cardiomyopathy are genetic, there is currently little understanding of how mutations lead to the disease, and there have been no new treatments developed in recent years. Dr. Murry and his team are utilizing patient-derived cells to generate human induced pluripotent stem cells (hiPSCs) from which heart muscle cells can be generated. These heart muscle cells have the exact genetic makeup (including the detrimental mutation) of the patient who donated the cells. Their goal is to use these hiPSCs to characterize the functional effects of the mutant heart muscle cells. They also want to identify novel therapeutic treatments that will enhance the function of heart muscle cells harboring these deleterious mutations.
- Lab-made heart tissue - Most of the work done with cells in culture is performed in a 2D environment; however, the heart and other organs develop and function in a 3D environment. In order to better mimic the heart for lab studies, Dr. Murry and his team are engineering 3D heart tissue constructs. This engineered heart tissue provides a platform to characterize contractile function and for the analysis of potentially novel therapeutic agents.
Dr. Murry knew he wanted to pursue a career in the medical field since the eighth grade. He has always had a love of science and a desire to serve humanity. He grew up in North Dakota, where his family raised horses. Spending time outside working with these animals gave him an appreciation for all living creatures and he felt a call to public service. While attending Duke University from 1982-1989, he spent his year of research in the pathology lab of one of his favorite professors, who happened to study the heart, and “got hooked”. Dr. Murry completed his residency and fellowship at the University of Washington School of Medicine where he ultimately opened his research lab with the Department of Pathology in 1996.
The heart is the worst organ in the body when it comes to the ability to repair itself, and heart disease is the leading cause of death for both men and women in the U.S. Dr. Murry has been personally affected by this disease. He lost his grandmother to a heart attack when he was a child and recently lost his mother to complications from heart disease. All of this prompted him to diligently study stem cell biology and cardiovascular disease for the past 20-25 years.