α1,3-Galactosyltransferase Gene-Knockout Pigs for Xenotransplantation: Where Do We Go From Here?

Cooper, D. K. C.; Dorling, Anthony; Pierson, Richard N.; Rees, Michael; Seebach, Jörg Dieter; Yazer, Mark H.; Ohdan, Hideki; Awwad, Michel; Ayares, David

doi:10.1097/01.tp.0000260427.75804.f2

Cited by 86 publications

(71 citation statements)

References 67 publications

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“…Using the above-mentioned approaches, pigs with highly sophisticated genetic modifications, including polytransgenic and α1,3GalT-KO pigs, have been produced, but they are far from optimal [86,[104][105][106][107]. In the future, breeding among multiple existing transgenic lines and introducing additional new genes by SCNT may be used in combination [103,108] to improve outcomes.…”

Section: Development Of Genetically Modified Pigs For Xenotransplantamentioning

confidence: 99%

Application of Genetically Modified and Cloned Pigs in Translational Research

Matsunari

Nagashima

2009

Journal of Reproduction and Development

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Abstract. Pigs are increasingly being recognized as good large-animal models for translational research, linking basic science to clinical applications in order to establish novel therapeutics. This article reviews the current status and future prospects of genetically modified and cloned pigs in translational studies. It also highlights pigs specially designed as disease models, for xenotransplantation or to carry cell marker genes. Finally, use of porcine somatic stem and progenitor cells in preclinical studies of cell transplantation therapy is also discussed. Key words: Cloned pig, Gene knockout, Transgenic pig, Translational research (J. Reprod. Dev. 55: [225][226][227][228][229][230] 2009) t present, pigs are not only considered important livestock but are also essential large-animal models in various types of biomedical research [1][2][3][4][5][6]. Furthermore, due to recent technological advances in genetic modification and somatic cell cloning, the range of applications for porcine models has increased markedly [7][8][9][10][11][12][13][14]. The present review focuses on development of genetically modified and cloned pigs and their use in translational studies.Translational research plays an important role as a bridge between basic science outcomes and the clinical realm, leading to development of novel therapeutics. However, disparate findings for rodent models and humans have hindered the translation of rodent data into actionable technologies for patients [15]. In contrast, pigs have many anatomical and physiological similarities to humans, including their cardiovascular systems, omnivorous gastrointestinal tracts and central nervous systems. Their physical sizes are also more comparable to that of humans, rendering pigs more appropriate for development of new surgical or endoscopic techniques.In the future, more advanced translational research may be conducted by improving the clinical relevance of pig models through genetic engineering. This article reviews the current status and future prospects of genetically modified pigs in preclinical studies of stem and progenitor cell therapy, the development of disease models and xenotransplantation.

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Section: Development Of Genetically Modified Pigs For Xenotransplantamentioning

confidence: 99%

Application of Genetically Modified and Cloned Pigs in Translational Research

Matsunari

Nagashima

2009

Journal of Reproduction and Development

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“…Pigs are currently considered to be the preferred source animal species for clinical xenoTx (7,8). If pig organs could be transplanted successfully into human patients, the advantages would be numerous.…”

Section: Despite the Increasing Use Of Livers From Living And Extendementioning

confidence: 99%

Impact of Thrombocytopenia on Survival of Baboons with Genetically Modified Pig Liver Transplants: Clinical Relevance

Ekser

Long

Echeverri

et al. 2010

American Journal of Transplantation

107

179

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A lack of deceased human donor livers leads to a significant mortality in patients with acute-on-chronic or acute (fulminant) liver failure or with primary nonfunction of an allograft. Genetically engineered pigs could provide livers that might bridge the patient to allotransplantation. Orthotopic liver transplantation in baboons using livers from a 1,3-galactosyltransferase gene-knockout (GTKO) pigs (n = 2) or from GTKO pigs transgenic for CD46 (n = 8) were carried out with a clinically acceptable immunosuppressive regimen. Six of 10 baboons survived for 4-7 days. In all cases, liver function was adequate, as evidenced by tests of detoxification, protein synthesis, complement activity and coagulation parameters. The major problem that prevented more prolonged survival beyond 7 days was a profound thrombocytopenia that developed within 1 h after reperfusion, ultimately resulting in spontaneous hemorrhage at various sites. We postulate that this is associated with the expression of tissue factor on platelets after contact with pig endothelium, resulting in platelet and platelet-peripheral blood mononuclear cell(s) aggregation and deposition of aggregates in the liver graft, though we were unable to confirm this conclusively. If this problem can be resolved, we would anticipate that a pig liver could provide a period during which a patient in liver failure could be successfully bridged to allotransplantation.

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“…12,13 If pig organs could be transplanted successfully into human patients, the advantages would be great. In this regard, immediate availability, perfect metabolic condition, adequate size-matching and hepatocyte mass, and freedom from potentially pathogenic microorganisms should be sought.…”

Section: Discussionmentioning

confidence: 99%