Life supporting function for over one month of a transgenic porcine heart in a baboon

Vial, Conrad; Ostlie, Daniel J.; Bhatti, Farah; Cozzi, Emanuele; Goddard, Martin; Chavez, Gilda; Wallwork, J.; White, David J.; Dunning, John

doi:10.1016/s1053-2498(99)00099-6

Cited by 110 publications

(64 citation statements)

References 11 publications

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“…To overcome immunological barriers, transgenic pigs bearing human complement-inhibiting proteins have been developed, leading to increased control of hyperacute rejection in primate models (8,13,19,24,31,41,47; M. Winkler, M. Loss, M. Przemeck, J. Schmidtko, H. Arends, R. Kunz, A. Jalali, J. Klempnauer, E. Cozzi, and D. J. G. White, Abstr. 5th Int.…”

mentioning

confidence: 99%

Study of Full-Length Porcine Endogenous Retrovirus Genomes with Envelope Gene Polymorphism in a Specific-Pathogen-Free Large White Swine Herd

Bosch¹,

Arnauld²,

Jestin³

2000

J Virol

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mentioning

confidence: 99%

Study of Full-Length Porcine Endogenous Retrovirus Genomes with Envelope Gene Polymorphism in a Specific-Pathogen-Free Large White Swine Herd

Bosch¹,

Arnauld²,

Jestin³

2000

J Virol

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“…Hearts from donor pigs transgenic for single complement regulators have survived up to 139 days as heterotopic grafts in non-human primates (Byrne et al, 2006) and up to 39 days as orthotopic transplants (Vial et al, 2000).…”

Section: Multi-transgenic Animalsmentioning

confidence: 99%

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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“…Several transgenic pigs expressing one or several human CRPs have been generated. Grafting of such human CRP transgenic organs into NHP animal models in both the absence or presence of immunosuppression demonstrated prolonged survival in a number of cases which is of clinical relevance for pig-to-human transplantation [61][62][63][64][65]. Importantly, incorporation of CD46, CD55 or CD59 into PERV particles resulted in a reduction of complement-mediated lysis of these particles in vitro [66,67].…”

Section: Inhibition Of Complement Activationmentioning

confidence: 99%

Reappraisal of biosafety risks posed by PERVs in xenotransplantation

Louz

Bergmans

Loos

et al. 2007

Reviews in Medical Virology

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Donor materials of porcine origin could potentially provide an alternative source of cells, tissues or whole organs for transplantation to humans, but is hampered by the health risk posed by infection with porcine viruses. Although pigs can be bred in such a way that all known exogenous microorganisms are eliminated, this is not feasible for all endogenous pathogens, such as the porcine endogenous retroviruses (PERVs) which are present in the germline of pigs as proviruses. Upon transplantation, PERV proviruses would be transferred to the human recipient along with the xenograft. If xenotransplantation stimulates or facilitates replication of PERVs in the new hosts, a risk exists for adaptation of the virus to humans and subsequent spread of these viruses. In a worst-case scenario, this might result in the emergence of a new viral disease. Although the concerns for disease potential of PERVs are easing, only limited pre-clinical and clinical data are available. Small-scale, well-designed and carefully controlled clinical trials would provide more evidence on the safety of this approach and allow a better appreciation of the risks involved. It is therefore important to have a framework of protective measures and monitoring protocols in place to facilitate such initially small scale clinical trials. This framework will raise ethical and social considerations regarding acceptability.

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Life supporting function for over one month of a transgenic porcine heart in a baboon

Cited by 110 publications

References 11 publications

Study of Full-Length Porcine Endogenous Retrovirus Genomes with Envelope Gene Polymorphism in a Specific-Pathogen-Free Large White Swine Herd

Study of Full-Length Porcine Endogenous Retrovirus Genomes with Envelope Gene Polymorphism in a Specific-Pathogen-Free Large White Swine Herd

Multi‐transgenic pigs for xenotransplantation

Reappraisal of biosafety risks posed by PERVs in xenotransplantation

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