[Xenotransplantation of solid organs].
Xenotransplantation von Organen.
Genetic engineering
Heart
Kidney
Organ preservation
Pilot study
Journal
Chirurgie (Heidelberg, Germany)
ISSN: 2731-698X
Titre abrégé: Chirurgie (Heidelb)
Pays: Germany
ID NLM: 9918383081906676
Informations de publication
Date de publication:
15 May 2024
15 May 2024
Historique:
accepted:
16
04
2024
medline:
15
5
2024
pubmed:
15
5
2024
entrez:
15
5
2024
Statut:
aheadofprint
Résumé
Transplantation of genetically modified porcine hearts and kidneys could become a solution to the persistent shortage of human organ donors. Progress has been made in genetic engineering of donor pigs, preservation techniques after organ harvesting and immunosuppression using co-stimulation blockade with anti-CD40/CD40L monoclonal antibodies. Progress has also been made in in the development of methods that detect pathogenic porcine viruses and prevent their transmission to the recipient. As normal land breed pig organs continue to grow in the recipient to their original size, different pig breeds (such as Auckland Island pigs) are now used which reach a final size suitable for humans. Alternatively, a knock-out of the growth hormone receptor gene has been established, e.g., in the 10GM genetically modified pigs from Revivicor/United Therapeutics, USA. The first clinical pilot studies including patients suffering from terminal heart failure are expected to start in Germany in about 2 years. Die Transplantation genetisch veränderter Schweineherzen und -nieren kann in den nächsten Jahren eine Lösung für den bestehenden Mangel an Organspendern darstellen. Fortschritte im Bereich des „Genetic Engineering“, aber auch verbesserte Organpräservationstechniken, eine Immunsuppression mit Kostimulationsblockade (Anti-CD40/CD40L-mAb) sowie eine verbesserte virologische Diagnostik, um eine Übertragung von pathogenen Schweineviren auf den Empfänger zu verhindern, haben hierzu beigetragen. Da Landrasse-Schweineorgane auch im Transplantatempfänger ihre Originalgröße erreichen, werden nun Schweinerassen verwendet, die entweder ein für den Menschen passendes Endgewicht erreichen (z. B. Auckland Island-Schweine) oder deren Wachstumshormonrezeptor genetisch inaktiviert wurde (z. B. in 10fach genetisch veränderten Schweinen der Fa. Revivicor/United Therapeutics, USA). Mit der ersten klinischen Pilotstudie an terminal Herzkranken wird in Deutschland in ca. 2 Jahren gerechnet.
Autres résumés
Type: Publisher
(ger)
Die Transplantation genetisch veränderter Schweineherzen und -nieren kann in den nächsten Jahren eine Lösung für den bestehenden Mangel an Organspendern darstellen. Fortschritte im Bereich des „Genetic Engineering“, aber auch verbesserte Organpräservationstechniken, eine Immunsuppression mit Kostimulationsblockade (Anti-CD40/CD40L-mAb) sowie eine verbesserte virologische Diagnostik, um eine Übertragung von pathogenen Schweineviren auf den Empfänger zu verhindern, haben hierzu beigetragen. Da Landrasse-Schweineorgane auch im Transplantatempfänger ihre Originalgröße erreichen, werden nun Schweinerassen verwendet, die entweder ein für den Menschen passendes Endgewicht erreichen (z. B. Auckland Island-Schweine) oder deren Wachstumshormonrezeptor genetisch inaktiviert wurde (z. B. in 10fach genetisch veränderten Schweinen der Fa. Revivicor/United Therapeutics, USA). Mit der ersten klinischen Pilotstudie an terminal Herzkranken wird in Deutschland in ca. 2 Jahren gerechnet.
Identifiants
pubmed: 38748210
doi: 10.1007/s00104-024-02093-y
pii: 10.1007/s00104-024-02093-y
doi:
Types de publication
English Abstract
Journal Article
Review
Langues
ger
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Längin M, Mayr T, Reichart B et al (2018) Consistent success in life-supporting porcine cardiac xenotransplantation. Nature 564:430–433
pubmed: 30518863
doi: 10.1038/s41586-018-0765-z
Reichart B, Längin M, Radan J et al (2020) Pig-to-non-human primate heart transplantation: The final step toward clinical xenotransplantation ? J Heart Lung Transplant 39:751–757
pubmed: 32527674
doi: 10.1016/j.healun.2020.05.004
Mohiuddin MM, Goerlich CE, Singh AK et al (2022) Progressive genetic modifications of porcine cardiac xenografts extend survival to 9 months. Xenotransplantation: e12744
Kim SC, Mathews DV, Breeden CP et al (2019) Long-term survival of rhesus macaque renal xenografts is dependent on CD4 T cell depletion. Am J Transplant 19:2174–2185
pubmed: 30821922
pmcid: 6658347
doi: 10.1111/ajt.15329
Ma D, Hirose T, Lassiter G et al (2022) Kidney transplantation from triple-knockout pigs expressing multiple human proteins in cynomolgus macaques. Am J Transplant 22:46–57
pubmed: 34331749
doi: 10.1111/ajt.16780
Griffith BP, Goerlich CE, Singh AK et al (2022) Genetically Modified Porcine-to-Human Cardiac Xenotransplantation. N Engl J Med 387:35–44
pubmed: 35731912
pmcid: 10361070
doi: 10.1056/NEJMoa2201422
Mohiuddin MM, Singh AK, Scobie L et al (2023) Graft dysfunction in compassionate use of genetically engineered pig-to-human cardiac xenotransplantation: a case report. Lancet 402:397–410
pubmed: 37393920
doi: 10.1016/S0140-6736(23)00775-4
Moazami N, Stern JM, Khalil K et al (2023) Pig-to-human heart xenotransplantation in two recently deceased human recipients. Nat Med 29(8):1989–1997
pubmed: 37488288
doi: 10.1038/s41591-023-02471-9
Loupy A, Goutadier V, Giarraputo A et al (2023) Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study. Lancet 402:1158–1169
pubmed: 37598688
doi: 10.1016/S0140-6736(23)01349-1
Novitzky D (1984) Electrocardiographic, hemodynamic and endocrine changes occurring during experimental brain death in the Chacma baboon. J Heart Transplant 4:63–69
Bery A, Marklin G, Itoh A et al (2022) The Specialized Donor Care Facility (SDCF) Model and Advances in Management of Thoracic Organ Donors. Ann Thorac Surg 113:1778–1786
pubmed: 33421385
doi: 10.1016/j.athoracsur.2020.12.026
Schmoeckel M (2000) Xenotransplantation hDAF-transgener Schweineherzen. Untersuchungen ex vivo und im Primatenmodell. Pabst Science Publishers
Cooper DKC, Hara H (2023) Xenotransplantation—a basic science perspective. Kidney 4:1147–1149
doi: 10.34067/KID.0000000000000173
Reichart B, Cooper DKC, Längin M et al (2022) Cardiac xenotransplantation: from concept to clinic. Cardiovasc Res 118:3499–3516
pmcid: 9897693
doi: 10.1093/cvr/cvac180
Byrne GW, McGregor CG (2012) Cardiac xenotransplantation: progress and challenges. Curr Opin Organ Transplant 17:148–154
pubmed: 22327911
pmcid: 3326642
doi: 10.1097/MOT.0b013e3283509120
Sykes M, Sachs DH (2019) Transplanting organs from pigs to humans. Sci Immunol. https://doi.org/10.1126/sciimmunol.aau6298
doi: 10.1126/sciimmunol.aau6298
pubmed: 31676497
pmcid: 7293579
Phelps CJ, Koike C, Vaught TD et al (2003) Production of alpha 1,3-galactosyltransferase-deficient pigs. Science 299:411–414
pubmed: 12493821
doi: 10.1126/science.1078942
Kwon DN, Lee K, Kang MJ et al (2013) Production of biallelic CMP-Neu5Ac hydroxylase knock-out pigs. Sci Rep 3:1981
pubmed: 23760311
pmcid: 4070623
doi: 10.1038/srep01981
Lutz AJ, Li P, Estrada JL et al (2013) Double knockout pigs deficient in N‑glycolylneuraminic acid and galactose alpha‑1,3‑galactose reduce the humoral barrier to xenotransplantation. Xenotransplantation 20:27–35
pubmed: 23384142
doi: 10.1111/xen.12019
Estrada JL, Martens G, Li P et al (2015) Evaluation of human and non-human primate antibody binding to pig cells lacking GGTA1/CMAH/beta4GalNT2 genes. Xenotransplantation 22:194–202
pubmed: 25728481
pmcid: 4464961
doi: 10.1111/xen.12161
Diamond LE, Quinn CM, Martin MJ et al (2001) A human CD46 transgenic pig model system for the study of discordant xenotransplantation. Transplantation 71:132–142
pubmed: 11211178
doi: 10.1097/00007890-200101150-00021
Cozzi E, White DJG (1995) The generation of transgenic pigs as potential organ donors for humans. Nat Med 1:964–966
pubmed: 7585226
doi: 10.1038/nm0995-964
Fodor WL, Williams BL, Matis LA et al (1994) Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute organ rejection. Proc Natl Acad Sci U S A 91:11153–11157
pubmed: 7526391
pmcid: 45185
doi: 10.1073/pnas.91.23.11153
Schmoeckel M, Cozzi E, Chavez G et al (1999) Xenotransplantation hDAF-transgener Schweineherzen. Zentralbl Chir 124:604–608
pubmed: 10474873
Wolf E, Schmoeckel M, Reichart B (2023) Cardiac xenotransplantation—from bench to bedside. Eur J Transplant 1:192–206
doi: 10.57603/EJT-305
Cooper DKC, Wang L, Kinoshita K et al (2023) Immunobiological barriers to pig organ xenotransplantation. Eur J Transplant 1:167–181
doi: 10.57603/EJT-266
Cowan PJ, Robson SC (2015) Progress towards overcoming coagulopathy and hemostatic dysfunction associated with xenotransplantation. Int J Surg 23:296–300
pubmed: 26220018
doi: 10.1016/j.ijsu.2015.07.682
Wuensch A, Baehr A, Bongoni AK et al (2014) Regulatory sequences of the porcine THBD gene facilitate endothelial-specific expression of bioactive human thrombomodulin in single-and multitransgenic pigs. Transplantation 97:138–147
pubmed: 24150517
doi: 10.1097/TP.0b013e3182a95cbc
Shu S, Ren J, Song J (2022) Cardiac xenotransplantation: a promising way to treat advanced heart failure. Heart Fail Rev 27:71–91
pubmed: 32572737
doi: 10.1007/s10741-020-09989-x
Mohiuddin MM, Reichart B, Byrne GW, McGregor CGA (2015) Current status of pig heart xenotransplantation. Int J Surg 23:234–239
pubmed: 26318967
pmcid: 4684783
doi: 10.1016/j.ijsu.2015.08.038
Steen S, Paskevicius A, Liao Q, Sjöberg T (2016) Safe orthotopic transplantation of hearts harvested 24 hours after brain death and preserved for 24 hours. Scand Cardiovasc J 50:193–200
pubmed: 26882241
pmcid: 4898163
doi: 10.3109/14017431.2016.1154598
Längin M, Reichart B, Steen S et al (2021) Cold non-ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig-to-baboon xenotransplantation. Xenotransplantation 28:e12636
pubmed: 32841431
doi: 10.1111/xen.12636
Bühler L, Basker M, Alwayn IP et al (2000) Coagulation and thrombotic disorders associated with pig organ and hematopoietic cell transplantation in nonhuman primates. Transplantation 70:1323–1331
pubmed: 11087147
doi: 10.1097/00007890-200011150-00010
Samy KP, Butler JR, Li P, Cooper DKC, Ekser B (2017) The Role of Costimulation Blockade in Solid Organ and Islet Xenotransplantation. J Immunol Res. https://doi.org/10.1155/2017/8415205
doi: 10.1155/2017/8415205
pubmed: 29159187
pmcid: 5660816
Reichart B, Längin M, Denner J et al (2021) Pathways to clinical cardiac xenotransplantation. Transplantation 105:1930–1943
pubmed: 33350675
doi: 10.1097/TP.0000000000003588
Anand RP, Layer JV, Heja D et al (2023) Design and testing of a humanized porcine donor for xenotransplantation. Nature 622:393–401
pubmed: 37821590
pmcid: 10567564
doi: 10.1038/s41586-023-06594-4
Längin M, Buttgereit I, Reichart B et al (2023) Xenografts Show Signs of Concentric Hypertrophy and Dynamic Left Ventricular Outflow Tract Obstruction After Orthotopic Pig-to-baboon Heart Transplantation. Transplantation 107:e328–e338
pubmed: 37643028
doi: 10.1097/TP.0000000000004765
Soin B, Ostlie D, Cozzi E et al (2000) Growth of porcine kidneys in their native and xenograft environment. Xenotransplantation 7:96–100
pubmed: 10961293
doi: 10.1034/j.1399-3089.2000.00046.x
Tanabe T, Watanabe H, Shah JA et al (2017) Role of intrinsic (graft) versus extrinsic (host) factors in the growth of transplanted organs following allogeneic and xenogeneic transplantation. Am J Transplant 17:1778–1790
pubmed: 28117931
pmcid: 5489354
doi: 10.1111/ajt.14210
Denner J (2022) Virus Safety of Xenotransplantation. Viruses 14:1926
pubmed: 36146732
pmcid: 9503113
doi: 10.3390/v14091926
Denner J (2017) The porcine virome and xenotransplantation. Virol J 14:171
pubmed: 28874166
pmcid: 5585927
doi: 10.1186/s12985-017-0836-z
Denner J, Schuurman HJ, Patience C (2009) The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes—chapter 5: Strategies to prevent transmission of porcine endogenous retroviruses. Xenotransplantation 16:239–248
pubmed: 19799764
doi: 10.1111/j.1399-3089.2009.00544.x
Meng XJ (2010) Hepatitis E virus: animal reservoirs and zoonotic risk. Vet Microbiol 140:256–265
pubmed: 19361937
doi: 10.1016/j.vetmic.2009.03.017
Denner J (2015) Xenotransplantation and Hepatitis E virus. Xenotransplantation 22:167–173
pubmed: 25676629
doi: 10.1111/xen.12156
Denner J, Bigley TM, Phan TL, Zimmermann C, Zhou X, Kaufer BB (2019) Comparative Analysis of Roseoloviruses in Humans, Pigs, Mice, and Other Species. Viruses 11:1108
pubmed: 31801268
pmcid: 6949924
doi: 10.3390/v11121108
Kotton CN, Torre-Cisneros J (2022) International CMV Symposium Faculty Cytomegalovirus in the transplant setting: Where are we now and what happens next? A report from the International CMV Symposium 2021. Transpl Infect Dis 24:e13977
pubmed: 36271650
pmcid: 10078482
doi: 10.1111/tid.13977
Denner J (2018) Reduction of the survival time of pig xenotransplants by porcine cytomegalovirus. Virol J 15:171
pubmed: 30409210
pmcid: 6225623
doi: 10.1186/s12985-018-1088-2
Denner J, Längin M, Reichart B et al (2020) Impact of porcine cytomegalovirus on long-term orthotopic cardiac xenotransplant survival. Sci Rep 10:17531
pubmed: 33067513
pmcid: 7568528
doi: 10.1038/s41598-020-73150-9
Denner J, Schuurman HJ (2022) Early testing of porcine organ xenotransplantation products in humans: Microbial safety as illustrated for porcine cytomegalovirus. Xenotransplantation 29:e12783
pubmed: 36336900
doi: 10.1111/xen.12783
Egerer S, Fiebig U, Kessler B et al (2018) Early weaning completely eliminates porcine cytomegalovirus from a newly established pig donor facility for xenotransplantation. Xenotransplantation 25:e12449
pubmed: 30264883
doi: 10.1111/xen.12449
Denner J, Tönjes RR (2012) Infection barriers to successful xenotransplantation focusing on porcine endogenous retroviruses. Clin Microbiol Rev 25:318–343
pubmed: 22491774
pmcid: 3346299
doi: 10.1128/CMR.05011-11
Halecker S, Krabben L, Kristiansen Y et al (2022) Rare isolation of human-tropic recombinant porcine endogenous retroviruses PERV-A/C from Göttingen minipigs. Virol J 19:30
pubmed: 35189916
pmcid: 8862210
doi: 10.1186/s12985-022-01742-0
Denner J, Schuurman HJ (2021) High Prevalence of Recombinant Porcine Endogenous Retroviruses (PERV-A/Cs) in Minipigs: A Review on Origin and Presence. Viruses 13:1869
pubmed: 34578447
pmcid: 8473008
doi: 10.3390/v13091869
Karlas A, Irgang M, Votteler J et al (2010) Characterisation of a human cell-adapted porcine endogenous retrovirus PERV-A/C. Ann Transplant 15:45–54
pubmed: 20657519
Fiebig U, Krüger L, Denner J (2024) Determination of the Copy Number of Porcine Endogenous Retroviruses (PERV) in Auckland Island Pigs Repeatedly Used for Clinical Xenotransplantation and Elimination of PERV‑C. Microorganisms 12:98
pubmed: 38257925
pmcid: 10820294
doi: 10.3390/microorganisms12010098
Denner J (2018) Why was PERV not transmitted during preclinical and clinical xenotransplantation trials and after inoculation of animals? Retrovirology 15:28
pubmed: 29609635
pmcid: 5879552
doi: 10.1186/s12977-018-0411-8
Kögel J, Marckmann G (2023) First-of-its-kind Xenotransplantation: Bedarf an ethischer Reflexion in Wissenschaft und Gesellschaft. Ethik Medizin 35:137–143
doi: 10.1007/s00481-023-00750-0
Caplan AN, Parent B (2022) Ethics and the emerging use of pig organs for xenotransplantation. J Heart Lung Transplant 41:1204–1206
pubmed: 35835681
doi: 10.1016/j.healun.2022.06.008
Schmoeckel M, Längin M, Reichart B et al (2023) Current status of cardiac xenotransplantation. Thorac Cardiovasc Surg. https://doi.org/10.1055/a-2235-8854
doi: 10.1055/a-2235-8854
Rossano JW, VanderPluym CJ, Peng DM et al (2021) Pedimacs Investigators. Fifth Annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) Report. Ann Thorac Surg 112:1763–1774
pubmed: 34648810
doi: 10.1016/j.athoracsur.2021.10.001
Goldstone AB, Bacha EA, Sykes M (2023) On cardiac xenotransplantation and the role of xenogeneic tolerance. J Thorac Cardiovasc Surg 166:968–972
pubmed: 36621453
doi: 10.1016/j.jtcvs.2022.11.036
Iwase H, Klein EC, Cooper DK (2018) Physiologic Aspects of Pig Kidney Transplantation in Nonhuman Primates. Comp Med 68:332–340
pubmed: 30208986
pmcid: 6200029
doi: 10.30802/AALAS-CM-17-000117
Tector AJ, Adams AB, Tector M (2023) Current status of renal xenotransplantation and next steps. Kidney 4:278–284
doi: 10.34067/KID.0007152021
Byrne GW (2018) Does human leukocyte antigens sensitization matter for xenotransplantation? Xenotransplantation 25:e12411. https://doi.org/10.1111/xen.12411
doi: 10.1111/xen.12411
pubmed: 29913037
pmcid: 6027985
Ladowski JM, Houp J, Hauptfeld-Dolejsek V et al (2021) Aspects of histocompatibility testing in xenotransplantation. Transpl Immunol 67:101409
pubmed: 34015463
pmcid: 8197754
doi: 10.1016/j.trim.2021.101409
Yamada K (2023) Revivicor United Therapeutics Symposium. Experience with 10GE pig kidneys and GalTKO thymokidneys towards clinical trials. In: IPITA-IXA-CTRMS Joint Congress. San Diego, CA, USA, S 25–28
Wang ZY, Reyes L, Estrada J (2023) Patients on the transplant waiting list have anti-swine leukocyte antigen class I antibodies. Immunohorizons. https://doi.org/10.4049/immunohorizons.2300056
doi: 10.4049/immunohorizons.2300056
pubmed: 38153351
pmcid: 10759154