Silencing porcine genes significantly reduces human-anti-pig cytotoxicity profiles: an alternative to direct complement regulation

Butler, James; Martens, Gregory R.; Estrada, José L.; Reyes, Luz M.; Ladowski, Joseph M.; Galli, Cesare; Perota, Andrea; Cunningham, Conor M.; Tector, Matthew; Tector, A. Joseph

doi:10.1007/s11248-016-9958-0

Cited by 46 publications

(35 citation statements)

References 30 publications

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“…We have also previously reported that fully allogeneic porcine VTL grafts in recipients treated with 28 days of tacrolimus facilitated induction of tolerance of VTL‐matched kidneys that were transplanted 3 months after VTL grafts without immunosuppression in a swine model . We will now combine these delayed XLTx strategies with a tolerance‐inducing preconditioning regimen which includes lung‐specific treatments, as well as utilizing new TGs donors to determine whether they will overcome the unique immunologic barriers in XLTx.…”

Section: Resultsmentioning

confidence: 98%

“…It is therefore clear that further strategies will be required to prolong lung graft survival from days to months. To protect the alveolar capillary network, in addition to adding hCD47 and other vascular protective genes as well as genes to reduce antigens against non‐Gal Abs, strategies to minimize inflammatory responses caused by pre‐formed Nab, macrophages, NK cells, T cells, and B cells must be considered prior to XLTx. We are currently exploring delayed lung transplantation in recipients that have received tolerance‐inducing preconditioning with lung‐specific strategies.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

GalT‐KO pig lungs are highly susceptible to acute vascular rejection in baboons, which may be mitigated by transgenic expression of hCD47 on porcine blood vessels

Watanabe

Sahara

Nomura

et al. 2018

Xenotransplantation

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

GalT‐KO pig lungs are highly susceptible to acute vascular rejection in baboons, which may be mitigated by transgenic expression of hCD47 on porcine blood vessels

Watanabe

Sahara

Nomura

et al. 2018

Xenotransplantation

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“…Expression of B4GALNT2 in human cells significantly increased antibodydependent complement-mediated lysis when these cells were challenged with serum from pig-to-baboon cardiac xenotransplantation sensitized recipient serum [25] while its deletion in pig PBMCs efficiently reduced human IgG and IgM binding and decreased human anti-porcine cytotoxicity [26,27]. The fact that a strong humoral response was detected in nonhuman primates receiving alginate-encapsulated islets especially against αGal [28,29] further emphasizes the necessity to use GGTA1-KO pigs as a background for other genetic modifications.…”

Section: Modification Of Donor Pigs To Mitigate the Immunementioning

confidence: 99%

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

Mourad

Gianello

2017

Curr Transpl Rep

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Purpose of Review Cell xenotransplantation has the potential to provide a safe, ethically acceptable, unlimited source for cell replacement therapies. This review focuses on genetic modification strategies aimed to overcome remaining hurdles standing in the way of clinical porcine islet transplantation and to develop neural cell xenotransplantation. Recent Findings In addition to previously described genetic modifications aimed to mitigate hyperacute rejection, instant blood-mediated inflammatory reaction, and cell-mediated rejection, new data showing the possibility of increasing porcine islet insulin secretion by transgenesis is an interesting addition to the array of genetically modified pigs available for xenotransplantation. Moreover, combining multiple modifications is possible today thanks to new, improved genomic editing tools. Summary Genetic modification of large animals, pigs in particular, has come a long way during the last decade. These modifications can help minimize immunological and physiological incompatibilities between porcine and human cells, thus allowing for better tolerance and function of xenocells.

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“…Today, research groups can produce multiple gene knock-out or knock-in pigs using CRISPR technology [87–94], which can also be used to delete PERV expression [74,95]. Genetically-modified pigs using CRIPSR technology have been used in several important studies relating to antibody binding [96–98] and coagulation dysfunction [99,100]. There are now more than 26 genetically-engineered pigs for xenotransplantation research (Table 2).…”

Section: Introductionmentioning

confidence: 99%

Xenotransplantation

Ekser

Li²,

Cooper³

2017

Current Opinion in Organ Transplantation

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Purpose of review To review the progress in the field of xenotransplantation with special attention to most recent encouraging findings which will eventually bring xenotransplantation to the clinic in the near future. Recent findings Starting from early 2000, with the introduction of Gal-knockout pigs, prolonged survival especially in heart and kidney xenotransplantation was recorded. However, remaining antibody barriers to nonGal antigens continue to be the hurdle to overcome. The production of genetically-engineered pigs was difficult requiring prolonged time. However, advances in gene editing, such as zinc finger nucleases, transcription activator-like effector nucleases, and most recently CRISPR technology made the production of genetically-engineered pigs easier and available to more researchers. Today, the survival of pig-to-nonhuman primate heterotopic heart, kidney, and islet xenotransplantation reached >900 days, >400 days, and >600 day, respectively. The availability of multiple-gene pigs (5 or 6 genetic modifications) and/or newer costimulation blockade agents significantly contributed to this success. Now, the field is getting ready for clinical trials with an international consensus. Summary Clinical trials in cellular or solid organ xenotransplantation are getting closer with convincing preclinical data from many centers. The next decade will show us new achievements and additional barriers in clinical xenotransplantation.

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Silencing porcine genes significantly reduces human-anti-pig cytotoxicity profiles: an alternative to direct complement regulation

Abstract: Silencing the GGTA1, CMAH and B4GalNT2 genes in pigs achieved a significant antigen reduction. Changing the porcine carbohydrate profile effectively mediates human antibody-mediated complement dependent cytoxicity.

Cited by 46 publications

References 30 publications

GalT‐KO pig lungs are highly susceptible to acute vascular rejection in baboons, which may be mitigated by transgenic expression of hCD47 on porcine blood vessels

GalT‐KO pig lungs are highly susceptible to acute vascular rejection in baboons, which may be mitigated by transgenic expression of hCD47 on porcine blood vessels

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

Xenotransplantation

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