Friday September 24, 2021 - 23:35 to 00:50
Examination of Life-Supporting Multi-Gene Cardiac Xenografts with GHRKO Reveals Contributors to Post-Transplantation Xenograft Growth
Corbin Goerlich1,4, Bartley Griffith1, Peter Hanna2, Susie Hong2, Avneesh Singh1, David Ayares3, Muhammad M. Mohiuddin1.
1Surgery, University of Maryland School of Medicine, Baltimore, MD, United States; 2Cardiology, University of Maryland School of Medicine, Baltimore, MD, United States; 3Revivicor, Inc, Blacksburg, VA, United States; 4Surgery, Johns Hopkins School of Medicine, Baltimore, MD, United States
Objective: Genetically engineered (GE) pigs are thought to be an alternative organ source for patients in end-stage heart failure unable to receive a timely allograft. However, cardiac xenografts exhibit growth and diastolic heart failure within one month after transplantation. Grafts function for up to 6 months, but only after administration of temsirolimus and afterload reducing agents to reduce this growth. Here we investigate the growth and hemodynamics of growth hormone receptor (GHR) knockout xenografts, without the use of adjuncts to prevent intrinsic graft growth after transplantation.
Methods: GE pig hearts were transplanted orthotopically into weight-matched baboons between 15-30kg, utilizing continuous perfusion preservation prior to implantation (n=5). Xenografts included knockout of carbohydrate antigens and knockin of human transgenes for thromboregulation, complement regulation and inflammation reduction (non-GHRKO, n=2). Three grafts contained the additional knockout of GHR (GHRKO, n=3). TTEs were obtained twice monthly and comprehensively analyzed by a blinded cardiologist. Hemodynamics were measured longitudinally after transplantation.
Results: All xenografts demonstrate life-supporting function after transplantation. There is no difference in intrinsic growth, as measured by septal and posterior wall thickness and LV mass, on TTE out to one month in either GHRKO or non-GHRKO grafts. However, hypertrophy of both the septal and posterior wall is markedly elevated by 2 months post-transplantation. There is minimal hypertrophy out to 6 months in GHRKO grafts. Physiologic mismatch is present in all grafts after transplantation, which is independent of growth.
Conclusions: Xenografts with GHRKO demonstrate reduced post-transplantation xenograft growth by echocardiography greater than 6 months after transplantation, without the need for other adjuncts.
Funding of this study is generously provided by public funding-NIH U19 AI090959 “Genetically-engineered Pig Organ Transplantation into Non-Human Primates” and private funding by United Therapeutics. David Ayares is an employee of Revivicor, Inc..