David Ayares’s research while affiliated with United Therapeutics Corporation and other places

Following our previous experience with cardiac xenotransplantation of a genetically modified porcine heart into a live human, we sought to achieve improved results by selecting a healthier recipient and through more sensitive donor screening for potential zoonotic pathogens. Here we transplanted a 10-gene-edited pig heart into a 58-year-old man with progressive, debilitating inotrope-dependent heart failure due to ischemic cardiomyopathy who was not a candidate for standard advanced heart failure therapies. He was maintained on a costimulation (anti-CD40L, Tegoprubart) blockade-based immunomodulatory regimen. The xenograft initially functioned well, with excellent systolic and diastolic function during the first several weeks posttransplantation. Subsequently, the xenograft developed rapidly progressing diastolic heart failure, biventricular wall thickening and, ultimately, near-complete loss of systolic function necessitating initiation of extracorporeal membranous oxygenation on day 31. Given these setbacks, the patient chose to transition to comfort care after 40 days. As with our first patient, histology did not reveal substantial immune cell infiltration but suggested capillary endothelial injury with interstitial edema and early fibrosis. No evidence of porcine cytomegalovirus replication in the xenograft was observed. Strategies to overcome the obstacle of antibody-mediated rejection are needed to advance the field of xenotransplantation.

Background Improvement in gene modifications of donor pigs has led to the prevention of early cardiac xenograft rejection and significantly prolonged cardiac xenograft survival in both heterotopic and orthotopic preclinical non-human primate (NHP) models. This progress formed the basis for FDA approval for compassionate use transplants in two patients. Methods Based on our earlier report of 9-month survival of seven gene-edited (7-GE) hearts transplanted (life-supporting orthotopic) in baboons, we transplanted 10 gene-edited pig hearts into baboons (n = 4) using non-ischemic continuous perfusion preservation (NICP) and immunosuppression regimen based on co-stimulation blockade by anti-CD40 monoclonal antibody. This pivotal study expands on the 7-GE backbone, with 3 additional gene edits, using 10-GE pigs as donors to baboon recipients. Results 10 GE cardiac xenografts provide life-supporting function up to 225 days (mean 128 ± 36 days) in a non-human primate model. Undetectable or latent porcine cytomegalovirus (PCMV) does not influence cardiac xenograft survival in this study but still needs more exploration with a larger cohort. Xenograft histology demonstrates adipose (Fat) deposition (n = 1), chronic vasculopathy (n = 1), micro and macro thrombosis, and acute cellular rejection (n = 1). Conclusions These data demonstrate that 10 GE cardiac xenografts have variable cardiac xenograft survival in NHP due to perhaps presence of 4th antigen and require further study. However, these 10GE organs may be suitable for clinical cardiac xenotransplantation and have already been utilized in two human cases.

Background Pleural effusions develop frequently after cardiac surgery in humans. Lung ultrasound is an essential non‐invasive tool in the diagnosis and treatment of these effusions. Pleural effusions also develop regularly after preclinical cardiac xenotransplantation experiments. Unlike in the human setting, modern ultrasound devices lack pre‐installed tools for calculating the volume of pleural effusions in baboons. The aim of this study was to analyze ultrasound examinations of pleural effusions after orthotopic pig‐to‐baboon cardiac xenotransplantation experiments in order to develop a formula for calculating the effusion volume based on ultrasound measurements. Methods Hearts from seven genetically modified (GGTA1‐KO, hCD46/hTBM transgenic) juvenile pigs were orthotopically transplanted into male baboons. Postoperatively, the baboons were tested regularly for the development of pleural effusions using ultrasound. When thoracocentesis was required, the drained effusion volume (EV) was compared to ultrasound‐derived calculations using various formulas. These calculations were based on measuring the distance between lung and diaphragm at the effusions’ maximum height (H max ). Subsequently, the most promising formula was used to describe the interobserver variability between trained and untrained staff members to predict effusion volumes based on ultrasound measurements. Results Ultrasound measurement correlated very strongly with the absolute EV ( r = 0.9156, p < 0.0001), with EV indexed to total body weight ( r = 0.9344, p < 0.0001) and with EV indexed to body surface area (BSA) ( r = 0.9394, p < 0.0001). The ratio between H max and EV increased with total body weight and BSA and also depended on the baboon species. The sonographic measurements taken by an experienced and an inexperienced observer showed only low interobserver variability. A Bland–Altman plot of both observers’ measurements showed an overall bias of –2.39%. Conclusion Ultrasound imaging provides a simple and non‐invasive tool for measuring pleural effusion quantity in baboons. This facilitates simple and efficient monitoring even in the hands of untrained personnel and may guide the decision‐making to perform thoracocentesis.