Friday September 24, 2021 - 23:35 to 00:50
Select Life-Supporting Multi-Gene Cardiac Xenografts from Swine Demonstrate Survival >8 months in Baboons, with Implications for Human Clinical Trials
Corbin Goerlich1,2, Bartley Griffith1, Avneesh K. Singh1, Tianshu Zhang1, Billeta Lewis1, Ivan Tatarov1, Faith Sentz1, Alena Hershfeld1, Patrick Odonkor3, Brittney Williams3, Erik Strauss3, Ali Tabatabai5, Adnan Bhutta4, David Ayares6, David Kaczorowksi1, Muhammad Mohiuddin1.
1Surgery, University of Maryland School of Medicine, Baltimore, MD, United States; 2Surgery, The Johns Hopkins School of Medicine, Baltimore, MD, United States; 3Anesthesia, University of Maryland School of Medicine, Baltimore, MD, United States; 4Pediatrics, University of Maryland School of Medicine, Baltimore, MD, United States; 5Medicine, Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD, United States; 6Revivicor, Inc, Blacksburg, VA, United States
Introduction: Cardiac xenotransplantation has been proposed to bridge the gap in organ shortage for those in end-stage heart failure without the opportunity to receive a heart. Recently, it has been shown that survival of a non-human primate recipient with a genetically engineered (GE) porcine- cardiac xenograft can be achieved up to 6 months in the orthotopic position with the addition of temsirolimus, blood pressure and heart rate control. We investigate an alternative means to achieve long-term survival, without the use of these adjuncts. We used “Multi-gene” edited pigs as xenograft donors with the addition of multiple human transgenes for complement regulation, thromboregulation, anti-inflammation and growth.
Methods: Baboons weighing 15-30 kg were used as recipients for life supporting cardiac xenografts. Weight-matched swine with multi-gene constructs were used as donors (table 1). Cardiac preservation was performed using an XVIVO© Perfusion system with XHS blood cardioplegia induction. Recipient blood pressure and heart rate were not controlled and temsirolimus was not administered after transplantation.
Results: Group 1 xenografts functioned well between 84-95 days, but ultimately succumbed to antibody mediated rejection and diastolic heart failure. Group 2 xenografts functioned well over 6 months. One was electively euthanized on post-transplant day #182 for histologic examination. The second recipient underwent an endomyocardial biopsy on post-transplant day #220, with survival ongoing >240 days exhibiting excellent graft function. Both demonstrated normal histology without evidence of rejection. Group 3 grafts exhibited survival up to 105 days, with survival ongoing in this cohort.
Conclusion: Xenografts with multiple transgenes and knockouts produce durable long-term survival and demonstrate pre-clinical efficacy to pursue the first human clinical trials. Consideration should be those with CMAHKO and GHRKO, but nuances remain in deciding what is best for pre-clinical models in baboons versus human clinical trials.
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..