Transgenic expression of human heme oxygenase‐1 in pigs confers resistance against xenograft rejection during ex vivo perfusion of porcine kidneys

Petersen, Björn; Ramackers, Wolf; Lucas‐Hahn, Andrea; Lemme, Erika; Hassel, Petra; Queisser, A. L.; Herrmann, Doris; Barg-Kues, Brigitte; Carnwath, Joseph Wallace; Klose, Johannes; Tiede, Andreas; Friedrich, Lars; Baars, Wiebke; Schwinzer, Reinhard; Winkler, Michael; Niemann, Heiner

doi:10.1111/j.1399-3089.2011.00674.x

Cited by 110 publications

(97 citation statements)

References 52 publications

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“…Recombinant rAAV.hHO-1 was produced using the triple transfection method as described previously (17) hHO-1.tg pigs were generated as described previously (22). Cloned syngenic offspring were used for the acute myocardial infarction pig model (Online Figures 1B and 2).…”

Section: Methodsmentioning

confidence: 99%

Heme Oxygenase-1 Gene Therapy Provides Cardioprotection Via Control of Post-Ischemic Inflammation

Hinkel

Lange

Petersen

et al. 2015

Journal of the American College of Cardiology

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Section: Methodsmentioning

confidence: 99%

Heme Oxygenase-1 Gene Therapy Provides Cardioprotection Via Control of Post-Ischemic Inflammation

Hinkel

Lange

Petersen

et al. 2015

Journal of the American College of Cardiology

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“…In mice, expression of human endothelial protein C receptor (hEPCR) on islets improved graft survival and function, reduced inflammation and coagulation, and allowed diabetes correction using less islets than required when wild-type mice were used as donors [37]. Antiapoptotic and anti-inflammatory molecules heme oxygenase-1 (HO-1) and A20 were shown to be efficient in preserving transgenic porcine endothelial cells against TNF-α-induced apoptosis [38,39]. In islets, expression of HO-1 prolonged pig-to-mouse graft survival and decreased immune cell infiltration and islet cell apoptosis [40].…”

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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“…Acute vascular rejection is characterized by endothelial activation, inflammation, thrombus formation and xenograft rejection. Petersen et al, (2011) and Yeom et al, (2012) showed that HO1 expression protects endothelial cells from TNF-α-mediated apoptosis, supports prolonged organ survival of porcine kidneys in ex vivo perfusion experiments with human blood, protects porcine fibroblasts from H2O2 damage and reduces TNF-α and cycloheximide-mediated apoptosis.…”

Section: Multi-transgenic Animalsmentioning

confidence: 99%

“…Several groups have produced HO1 transgenic pigs. Petersen et al (2011) generated transgenic pigs with SV40 promoter driven HO1…”

Section: Heme Oxygenasementioning

confidence: 99%

“…Both methods verified high HO1 protein levels. The SV40-HO1 construct was also used for the generation of HO1 expressing pigs by Petersen et al, (2011). It was reported that porcine fibroblasts were electroporated with the HO1 plasmid, resulting in random integration of an unknown copy number at an unknown number of integration sites.…”

Section: Rosa26 Targeting and Expression Of Ho1mentioning

confidence: 99%

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Multi‐transgenic pigs for xenotransplantation

Fischer

Kraner-Scheiber

Flisikowski

et al. 2013

Xenotransplantation

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Genetically modified pigs offer a solution to the severe shortage of organs available for human transplantation. Inactivation of the α1,3‐galactosyltransferase gene, responsible for α1,3‐Gal epitope synthesis (1–2) was a major breakthrough and essentially solved the problem of hyperacute rejection. However, further modifications of donor pigs are required to enable long term xenograft survival. These include expression of complement regulatory, antithrombotic, endothelium protective and immuno‐regulatory transgenes. Current evidence indicates that complement regulator transgenes, such as CD46 and CD55, must be expressed at least fivefold more than their human endogenous equivalent to effectively protect grafted tissue (3). To explore means of achieving high expression, we produced a series of BAC‐ and PAC‐vector constructs containing different sized genomic complement regulatory genes, from 70 to 190 kb, under the control of endogenous or CAGGs (CMV enhancer chicken β actin) promoter sequences. Using these vectors we obtained high levels of CD46 and CD55 expression in vitro. To prepare multi‐transgene “packages” for introduction into animals, the most effective constructs were combined with one or two further xenoprotective transgenes, including A20 (4), HO‐1 (5), thrombomodulin (6) and CTLA4‐Ig (LEA 29Y). In cotransfection experiments single cell clones expressing up to five different xenogenes could be detected. Achieving desired levels of transgene expression in an animal is not only a function of the transgene construct, but also of the location at which it integrates. Position effect variation in expression of random transgenes is well‐documented. Transgene placement by gene targeting at a permissive locus offers a useful means of achieving reliable transgene expression. In mice the ROSA26 locus is widely used to support ubiquitous expression of inserted transgenes (7–8). Murine ROSA26 encodes no functional genes and extensive gene targeting of this locus has not led to deleterious effects on development or physiology (9). To enable a similar approach in pigs, we recently identified a strong candidate for the porcine ROSA26 locus. Gene targeted placement of a neomycin reporter gene construct under the control of the ROSA26 promoter showed expression in all examined porcine tissues of all three germ layers. This strongly suggests that porcine ROSA 26 may resemble the murine locus as a suitably permissive site for transgene expression. We are currently proceeding with gene targeting to place various xenoprotective transgene constructs at this locus. References: 1. Dai Y, Vaught TD, Boone J et al. Targeted disruption of the alpha1,3‐ galactosyltransferase gene in cloned pigs. Nat Biotechnol 2002; 20: 251–255. 2. Lai L, Kolber‐Simonds D, Park K et al. Production of alpha‐1,3‐galactosyltransferase knockout pigs by nuclear transfer cloning. Science 2002; 295: 1089–1092. 3. Miyagawa S, Fukuta D, Kitano E et al. Effect of tandem forms of DAF(CD55) on complement‐mediated xenogeneic cell lysis. Xenotransplantation 20...

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Transgenic expression of human heme oxygenase‐1 in pigs confers resistance against xenograft rejection during ex vivo perfusion of porcine kidneys

Abstract: These results are encouraging and warrant further studies on the biological function of heme oxygenase-I expression in hHO-1 transgenic pigs in the context of xenotransplantation.

Cited by 110 publications

References 52 publications

Heme Oxygenase-1 Gene Therapy Provides Cardioprotection Via Control of Post-Ischemic Inflammation

Heme Oxygenase-1 Gene Therapy Provides Cardioprotection Via Control of Post-Ischemic Inflammation

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

Multi‐transgenic pigs for xenotransplantation

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