Overcoming the Translational Challenges of Using Pluripotent Stem Cells for Therapy in an Ischemic Cardiomyopathy Model
Five million people in the United States suffer with heart failure, resulting in ~60,000 deaths at a cost of $30 billion/year. These patients also are more prone to sudden cardiac death, causing ~500,000 deaths annually. In addition, ~80,000 children are born each year in the United States with congenital heart disease, the most common human birth defect, and many of these children eventually develop heart failure. Heart failure occurs when the heart is damaged and becomes unable to meet the demands placed on it. Unlike other organs, the heart is unable to fully repair itself after injury. Despite advances over the past two decades, it is rarely possible to rescue heart muscle from some degree of irreversible injury and death after a heart attack, and none of the currently accepted therapies replace damaged heart muscle with new heart cells. Human embryonic stem cells (hESCs) grow and divide indefinitely while maintaining the potential to develop into many tissues of the body, including heart muscle. They provide an unprecedented opportunity to advance new cell-based therapies for heart attack and heart failure. We have developed methods for identifying and isolating specific types of hESCs, stimulating them to become human heart muscle cells, delivering these into the hearts of mice after heart attack, and assessing their functional benefits. However, to advance this therapy to human patients, studies must be carried out in large animal models that closely mimic the human disease, and a number of major bottlenecks must be overcome. In this proposal, we will use a model of heart attack in the pig that closely resembles the human disease to address these bottlenecks. We will evaluate how the recipient animal’s immune system responds to hESC therapy and develop ways to modulate this response; develop methods to increase the local retention and survival of hESC cells after delivery into the heart; and assess the safety hESC therapy with regard to heart function, rhythm and tumor formation. These studies also are designed to generate solutions that will allow us to bring hESC therapy not only to heart attack victims, but to those bearing the burden of other diseases where organs are damaged or not functioning properly.
Heart failure is very common with ~100,000 people in California suffering from this condition at a cost of ~$540 million/year. In addition, ~11,000 children are born in California each year with congenital heart disease, the most common human birth defect. Many will develop heart failure at an additional cost of ~$75 million/year. Heart failure occurs when the heart is damaged and becomes unable to meet the demands placed on it. Unlike other organs, the heart is unable to repair itself. Our group has developed methods for identifying and isolating specific types of human embryonic stem cells (hESCs), stimulating them to become human heart muscle cells, delivering these into the hearts of rodents after myocardial infarction, and assessing their retention and ability to couple electrically and functionally to the myocardium. The current proposal will move our group’s accomplishments forward in a large animal (porcine) pre-clinical model designed to address translational bottleneck issues. To this end, we have assembled a multidisciplinary team of seasoned co-investigators and consultants, including basic scientists, biomedical engineers, cardiologists, immunologists, pathologists, electrophysiologists, and human clinical trials experts to successfully address the Aims in this proposal, and pave the way for advancing this novel therapy to patients. Even though we propose to use an ischemic cardiomyopathy model of heart failure as a way to address the bottleneck issues relevant to hESC therapy for human disease, we fully expect our research to generate solutions that could be applicable to the development of therapies for other human diseases characterized by organ damage or insufficiency. In addition to the health benefits to the people of California, and the anticipated savings in health care costs, these studies will lead to therapeutic technologies that could be used by the state and its biopharmaceutical industry to increase its tax base. This research also will push the field of regenerative medicine forward despite the paucity of federal funds and better prepare us to utilize these funds when they become available in the future.