A major advance toward clinical cardiac xenotransplantation

Pierson, Richard N.

doi:10.1016/j.jtcvs.2019.04.087

Cited by 9 publications

(9 citation statements)

References 21 publications

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“…This was setting a very high bar, and it consequently took 20 y to fulfill these requirements. 12,13,91,92 In our opinion, 4 steps are necessary for future successful clinical cardiac xenotransplantation: (i) Stable expression of xenoprotective transgenes to prevent hyperacute and delayed humoral rejection or signs of microangiopathy (see the Pigs as Organ Donors-Physiological and Immunological Aspects section). (ii) Clinically safe (nonnephrotoxic) immunosuppression.…”

Section: Clinical Cardiac Xenotransplantationmentioning

confidence: 99%

Pathways to Clinical Cardiac Xenotransplantation

Reichart¹,

Längin

Denner

et al. 2021

Transplantation

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Heart transplantation is the only long-lasting lifesaving option for patients with terminal cardiac failure. The number of available human organs is however far below the actual need, resulting in substantial mortality of patients while waiting for a human heart. Mechanical assist devices are used to support cardiac function but are associated with a high risk of severe complications and poor quality of life for the patients. Consistent success in orthotopic transplantation of genetically modified pig hearts into baboons indicates that cardiac xenotransplantation may become a clinically applicable option for heart failure patients who cannot get a human heart transplant. In this overview, we project potential paths to clinical cardiac xenotransplantation, including the choice of genetically modified source pigs; associated requirements of microbiological, including virological, safety; optimized matching of source pig and recipient; and specific treatments of the donor heart after explantation and of the recipients. Moreover, selection of patients and the regulatory framework will be discussed.

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Section: Clinical Cardiac Xenotransplantationmentioning

confidence: 99%

Pathways to Clinical Cardiac Xenotransplantation

Reichart¹,

Längin

Denner

et al. 2021

Transplantation

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“…Since the latest survival of orthotopic cardiac xenotransplantation in pre‐clinical models approaches 200 days, the consideration to initiate clinical trials has now become relevant 17,146 . The physiologic role of the heart is less complex than the kidney however the outcome in case of failure is much more difficult to manage.…”

Section: Selecting the Ideal Recipient Candidate For First Clinical Trialsmentioning

confidence: 99%

Recent progress and remaining hurdles toward clinical xenotransplantation

Meier

Longchamp

Mohiuddin

et al. 2021

Xenotransplantation

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Background Xenotransplantation has made tremendous progress over the last decade. Methods We discuss kidney and heart xenotransplantation, which are nearing initial clinical trials. Results Life sustaining genetically modified kidney xenografts can now last for approximately 500 days and orthotopic heart xenografts for 200 days in non‐human primates. Anti‐swine specific antibody screening, preemptive desensitization protocols, complement inhibition and targeted immunosuppression are currently being adapted to xenotransplantation with the hope to achieve better control of antibody‐mediated rejection (AMR) and improve xenograft longevity. These newest advances could probably facilitate future clinical trials, a significant step for the medical community, given that dialysis remains difficult for many patients and can have prohibitive costs. Performing a successful pig‐to‐human clinical kidney xenograft, that could last for more than a year after transplant, seems feasible but it still has significant potential hurdles to overcome. The risk/benefit balance is progressively reaching an acceptable equilibrium for future human recipients, e.g. those with a life expectancy inferior to two years. The ultimate question at this stage would be to determine if a “proof of concept” in humans is desirable, or whether further experimental/pre‐clinical advances are still needed to demonstrate longer xenograft survival in non‐human primates. Conclusion In this review, we discuss the most recent advances in kidney and heart xenotransplantation, with a focus on the prevention and treatment of AMR and on the recipient’s selection, two aspects that will likely be the major points of discussion in the first pig organ xenotransplantation clinical trials.

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“…For the purposes of this personal viewpoint, we assume that a therapeutic approach—a defined pig phenotype and clinically acceptable drug regimen—will soon be identified in preclinical studies that is consistently associated with long‐term (>6 months) survival of orthotopic heart xenograft recipients 4–8 . We anticipate that renal xenograft clinical trials may advance more rapidly, with return to dialysis available for recipient “rescue” in case of graft failure; if so, results will inform design and conduct of initial heart trials.…”

Section: Rationale For Cardiac Xenotransplantationmentioning

confidence: 99%

“…Baboon recipients of life-supporting orthotopic pig xenografts have survived to elective termination beyond 6 months. 4 This progress has derived from better understanding of the pathophysiology of "delayed xenograft rejection," including "thrombotic microangiopathy" and "consumptive coagulopathy," [6][7][8] which are effectively addressed by genetic engineering of "donor" pigs 4,7,9 and costimulation pathway blockade. 4,7,10,11…”

Section: Recent Preclini C Al Advan Ce Smentioning

confidence: 99%

“…For the purposes of this personal viewpoint, we assume that a therapeutic approach-a defined pig phenotype and clinically acceptable drug regimen-will soon be identified in preclinical studies that is consistently associated with long-term (>6 months) survival of orthotopic heart xenograft recipients. [4][5][6][7][8] We anticipate that renal xenograft clinical trials may advance more rapidly, with return to dialysis available for recipient "rescue" in case of graft failure; if so, results will inform design and conduct of initial heart trials. On the other hand, currently available treatments are associated with such poor outcomes for some end-stage heart failure patients that proceeding first with heart xenografts may be justified, presuming careful, deliberate patient selection.…”

Section: Introductionmentioning

confidence: 99%

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Pig-to-human heart transplantation: Who goes first?

Pierson

Burdorf

Madsen

et al. 2020

American Journal of Transplantation

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Scarcity of hearts from human donors is the major factor constraining expanded application of cardiac transplantation. Each year >7% of the ≈4000 patients on the United Network for Organ Sharing waiting list die resulting from the unavailability of a suitable human donor heart. 1,2 Use of "expanded criteria" donors, including those at increased risk for transmitting a communicable infectious disease, and hearts resuscitated ex vivo following "donation after cardiac death," appear to be feasible and are being evaluated in clinical trials, but cannot adequately address the large, unmet need. 3 2 | R ATI ONALE FOR C ARD IAC XENOTR ANS PL ANTATION The use of pigs as a source of hearts for use as "xenografts" in humans (cardiac xenotransplantation) could potentially address the current donor heart shortfall. If predictably healthy organs were dependably available when needed, many patients who are currently not offered

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A major advance toward clinical cardiac xenotransplantation

Cited by 9 publications

References 21 publications

Pathways to Clinical Cardiac Xenotransplantation

Pathways to Clinical Cardiac Xenotransplantation

Recent progress and remaining hurdles toward clinical xenotransplantation

Pig-to-human heart transplantation: Who goes first?

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