Humanized Cardiovascular Organs in Gene Edited Pigs
Abstract
PRMRP Areas of Encouragement: (1) congenital heart disease (CHD), (2) cardiomyopathy, (3) tissue regeneration, and (4) novel approaches to address immune rejection following transplantation Objectives and Rationale: CHD and advanced heart failure are common and deadly. Cardiovascular disease is the number one cause of death worldwide and in the U.S. Cardiac transplantation is the only cure for heart failure, and demand for hearts is significantly greater than the supply of donor hearts. It is estimated that each year only 2% of individuals that need a heart transplant receive this lifesaving therapy (in the U.S.) due to the limited supply of donor hearts, which has not changed in number over the past 40-year period. Those patients that receive a heart transplant require lifelong immunosuppression, which is associated with deleterious side effects. Moreover, the survival of the transplanted heart is dependent on its associated vasculature. Collectively, these challenges support the notion that new therapies are warranted. In addition, battlefield casualty and trauma often result in major cardiovascular injury and blood loss, resulting in significant and chronic injuries and/or death. The battlefield injuries also commonly result in vascular injuries and blood loss. Therefore, we anticipate that the humanized heart-vasculature (blood) tissues will be an invaluable source of organs and blood for the treatment of injured Soldiers, military personnel, and Veterans. Goals of Research: The overall goal for this research proposal is to genetically engineer pig embryos that lack a heart and its vasculature (blood) and rescue these pig embryos with personalized human stem cells (hiPSCs) that will efficiently and completely produce a humanized heart and its associated vasculature (and blood) in a viable pig. The ability to engineer humanized vasculature will prevent hyperacute rejection of whole heart transplants for the treatment of CHD and advanced heart failure. Moreover, these genetically engineered pigs will serve as an unlimited source for human vascular conduits and human blood. The successful achievement of our aims will result in the development of two unprecedented products: (1) a humanized heart-vascular model in a pig to test new treatments and (2) an unlimited supply of human hearts (and associated human vasculature) to treat acute and chronic diseases incurred on the battlefield or in our Veteran population. These products will address an unmet need for some of the most significantly wounded Service Members evacuated from current conflicts and our Veteran population. Research Applicability: The proposed work directly addresses the FY20 PRMRP Areas of Encouragement pertaining to: (1) CHD, (2) cardiomyopathy, (3) tissue regeneration, and (4) novel approaches to address immune rejection following transplantation, which respectively represent the immediate and long-term benefits of this work. Approximately 14,500 Service Members were evacuated from war between 2001 and 2013, and about 77% had some form of cardiovascular injury. These injuries contribute to a total lifetime cost of $108.8 billion in disability benefits to injured Service Members and require extended and prolonged hospitalization and rehabilitation times. The research proposed in the current grant application provides an ambitious and innovative approach to generate human organs and blood that will have an immediate impact at the time of injury and have a long-term impact in the survival and quality of life experienced by injured Soldiers, Veterans, and patients. Service Member Benefit: CHD and cardiovascular diseases impact the mortality and the morbidity of our military personnel and Veteran patient population. As cardiovascular injuries and blood loss impact the survival of Soldiers on the battlefield, new therapies are warranted. Combat casualties cost the DoD billions of dollars in initial costs and in lifetime disability benefit cost to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110606
Entities
People
- Daniel J Garry
Organizations
- United States Army
- University of Minnesota