Abstract
Cardiac xenotransplantation (CXTx) is a promising solution to the chronic shortage of donor hearts. Recent advancements in immune suppression have greatly improved the survival of heterotopic CXTx, now extended beyond 2 years, and life-supporting kidney XTx. Advances in donor genetic modification (B4GALNT2 and CMAH mutations) with proven Gal-deficient donors expressing human complement regulatory protein(s) have also accelerated, reducing donor pig organ antigenicity. These advances can now be combined and tested in life-supporting orthotopic preclinical studies in nonhuman primates and immunologically appropriate models confirming their efficacy and safety for a clinical CXTx program. Preclinical studies should also allow for organ rejection to develop xenospecific assays and therapies to reverse rejection. The complexity of future clinical CXTx presents a substantial and unique set of regulatory challenges which must be addressed to avoid delay; however, dependent on these prospective life-supporting preclinical studies in NHPs, it appears that the scientific path forward is well defined and the era of clinical CXTx is approaching.
Highlights
About 5.7 million Americans have heart failure, half of whom will die within 5 years [1]
The longest reported survival was 99 days using hDAF transgenic hearts [29]. These results demonstrated that expression of human complement regulatory proteins (hCRPs) was sufficient to abrogate the need for systemic complement inhibition, but was not sufficient to prevent an induced antibody response and antibody-mediated rejection (AMR)
Based on the high frequency of AMR, the wide diversity of potential polymorphic porcine peptides and the chronic detection of vascular antibody deposition in GTKO donor hearts, it is necessary to establish methods for early diagnosis and effective treatment. It appears that anti-CD40-based immune suppression, which is likely to be used in clinical CXTx, relies heavily on effective costimulation blockade, as withdrawal of anti-CD40 therapy has resulted in the induction of non-Gal IgM and IgG [8]
Summary
About 5.7 million Americans have heart failure, half of whom will die within 5 years [1]. There has been a remarkable improvement in survival of heterotopic pig-to-nonhuman primate (NHP) CXTx [5,6,7,8], encouraging early success in orthotopic CXTx (oCXTx) [9,10,11] and advances in lifesupporting renal xenotransplantation (RXTx) [12, 13] These results validate the physiological compatibility of porcine organs, at least in NHPs, and suggest that clinical CXTx may soon be applicable if oCXTx can attain similar improvements in survival as RXTx. In this review, we examine developments in immune suppression, porcine donor genetics, preclinical transplants, and infectious disease issues and discuss requirements for clinical CXTx. To justify a clinical xenotransplantation (XTx) program, it is necessary to demonstrate transplant efficacy in clinically relevant animal models. All combinations of donor genetics and immune suppression have not been reported, as perceived advances in donor genetics were seldom tested with reduced or previous immune suppression techniques
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