Cardiac Xenotransplantation: Progress in Preclinical Models and Prospects for Clinical Translation

Abstract

Survival of pig cardiac xenografts in a non-human primate (NHP) model has improved significantly over the last 4 years with the introduction of costimulation blockade based immunosuppression (IS) and genetically engineered (GE) pig donors. The longest survival of a cardiac xenograft in the heterotopic (HHTx) position was almost 3 years and only rejected when IS was stopped. Recent reports of cardiac xenograft survival in a life-sustaining orthotopic (OHTx) position for 6 months is a significant step forward. Despite these achievements, there are still several barriers to the clinical success of xenotransplantation (XTx). This includes the possible transmission of porcine pathogens with pig donors and continued xenograft growth after XTx. Both these concerns, and issues with additional incompatibilities, have been addressed recently with the genetic modification of pigs. This review discusses the spectrum of issues related to cardiac xenotransplantation, recent progress in preclinical models, and its feasibility for clinical translation.

A Standardized Approach to Orthotopic (Life-supporting) Porcine Cardiac Xenotransplantation in a Nonhuman Primate Model

“…It requires a multidisciplinary team of scientists, immunologists, clinical staff, surgeons, and perfusionists with expertise and experience working with NHPs and heart transplant recipients. 38 However, this is a robust preclinical model of cardiac xenotransplantation with immediate translational potential even if appropriate FDA approval is required. [39][40][41][42][43] Moreover, postoperative protocolization, although specifically optimized for cardiac xenotransplantation, can be applied to cardiac allotransplantation and other disciplines of transplantation using NHP models.…”

Organ Reconditioning and Machine Perfusion in Transplantation

“…In the present issue, we touched upon the whole spectrum of thoracic and abdominal transplant surgery: from heart preservation (Qin et al), whose valuable contribution was key to allow the first cardiac xenograft to happen (7), to normothermic lung perfusion, enriched by precise measurement of exhaled endogenous CO (Brenckmann et al), to provide an additional early marker in lung grafts evaluation, moving toward the current trends in preservation solutions for pancreas ( decision to implant a non-standard criteria graft. This leads roughly to a 20% liver and kidney discard, based on the transplant provider's judgement, rather than following objectively identifiable scores, which are currently not available for most of the areas discussed.…”

“…In the present issue, we touched upon the whole spectrum of thoracic and abdominal transplant surgery: from heart preservation ( Qin et al ), whose valuable contribution was key to allow the first cardiac xenograft to happen ( 7 ), to normothermic lung perfusion, enriched by precise measurement of exhaled endogenous CO ( Brenckmann et al ), to provide an additional early marker in lung grafts evaluation, moving toward the current trends in preservation solutions for pancreas ( Ferrer-Fàbrega et al ), for normothermic kidney and hypothermic combined kidney-liver technologies ( Fard et al ; Chang et al ), and describing the first proof-of-concept pilot study for liver viability assessment, via hyperspectral imaging ( Fodor et al ).…”

Cardiac Surgeons Highlight the Need for Innovation Stewardship: Noteworthy in 2022

“…For this reason, initial attempts of xenotransplantation had graft survival measured in minutes or days. 7…”

“…For this reason, initial attempts of xenotransplantation had graft survival measured in minutes or days. 7 Genetic engineering can prevent activation of these preformed antibodies and thus prevent early graft failure from coagulation dysfunction, as demonstrated by Mohiuddin et al 8 Novel gene-editing technologies like CRISPR-Cas9 permit the development of knock out strains that lack immunogenic epitopes-such as α1-3-galactose, Sda blood group antigen, and N-glycolylneuraminic acid-while also inserting human complement inhibitory proteins and thrombomodulin. Reviewing the impressive progress made by genetic engineering in further detail is beyond the scope of this review.…”