doi: 10.15389/agrobiology.2014.2.42eng

UDC 636.44:[573.6.086.83+577.21]:616-089.843

APPLICATION OF GAL-KO TRANSGENIC PIGS IN XENOTRANSPLANTATION: PROBLEMS AND PROSPECTS FOR THE FUTURE

N.A. Zinovieva1, A.V. Melerzanov2, E.V. Petersen2, N. Klymiuk3, N.A. Volkova1, A.S. Dukh2, I.A. Trusova2, E. Wolf3, G. Brem4

1All-Russian Research Institute of Animal Husbandry, Russian Academy of Agricultural Sciences,
pos. Dubrovitsy, Podolsk Region, Moscow Province, 142132 Russia,
e-mail: n_zinovieva@mail.ru, natavolkova@inbox.ru
2Moscow Institute of Physics and Technology, State University,
9, Institutskii per., Dolgoprudnyi, Moscow Province, 141700 Russia,
e-mail:  m83071@gmail.com, petersen.elena.v@gmail.com, a.s.dukh@gmail.com, innatrusova@gmail.com
3Institute of Molecular Animal Breeding and Biotechnology LMU,
Feodor-Lynen Str. 25, 81377 Munich, Germany,
e-mail: N.Klymiuk@gen.vetmed.uni-muenchen.de, ewolf@lmb.uni-muenchen.de
4Institute of Animal Breeding and Genetics, VMU,
Veterinärplatz, A-1210, Vienna, Austria,
e-mail: gottfried.brem@agrobiogen.de

Received January 15, 2014


Xenotransplantation (сross-species transplantation) has a great potential to serve the needs for organs, tissues and cells for transplantation. In this review, the applications of genetically modified pigs as the donors of organs and tissues for clinical transplantation are discussed. The hyperacute rejection (HAR) process is shortly described. One of the ways to overcome HAR is the creation of pigs lacking alpha-1,3-galactosyltransferase (alpha-1,3-GalT) epitopes — the major xenoantigene in pig-to-primate organ xenotransplantation. The analysis of the efficiency of targeting the alpha-1,3-galactosyltransferase gene (GGTA1) in porcine cells by using different methods was performed: the targeting efficiency (the number of piglets carrying the knock-out of GGTA1 born alive from the number of the cloned embryos transferred) is differed between laboratories and varied of 0.0 to 5.0 per cent. The different techniques used for the development of transgenic pigs lacking GGTA1 (GAL-KO pigs) are shortly described. The possible applications of organs and tissues of GAL-KO pigs for xenotransplantation are overviewed. The advantages of using of the skin derived from GAL-KO pigs as a potential alternative for a temporary cover of burns comparing to the alloskin and skin derived from the normal (GAL-positive) pigs are shown. Uses of GAL-KO pigs as donors of heart valves are briefly reviewed. The research aims for the future are discussed.

Keywords: transgenic pigs, GAL-KO, xenotransplantation, organs and tissues donors, skin transplantation, heart valves of pigs.

 

Full article (Rus)

 

REFERENCES

1. Shumakov V., Tonevitskii A. Chelovek, 1999, 6.

2. Yang Y.G., Sykes M. Xenotransplantation: Current status and a perspective on the future. Nat. Rev. Immunol., 2007, 7: 519-531. CrossRef

3. Polejaeva I.A., Chen S.H., Vaught T.D., Page R.L., Mullins J., Ball S., Dai Y., Boone J., Walker S., Ayares D.L., Colman A., Campbell K.H. Cloned pigs produced by nuclear transfer from adult somatic cells. Nature, 2000, 407: 86-90. CrossRef

4. Klymiuk N., Aigner B., Brem G., Wolf E. Genetic modification of pigs as organ donors for xenotransplantation. Mol. Reprod. Dev., 2010, 77(3): 209-221.

5. Denning C., Dickinson P., Burl S., Wylie D., Fletcher J., Clark A.J. Gene targeting in primary fetal broblasts from sheep and pig. Cloning Stem Cells, 2001, 3: 221-231.

6. Harrison S., Boquest A., Grupen C., Faast R., Guildolin A., Giannakis C., Crocker L., McIlfatrick S., Ashman R., Wengle J., Lyons I., Tolstoshev P., Cowan P., Robins A., O'Connell P., d'Apice A.J., Nottle M. An efficient method for producing alpha(1,3)-galactosyltransferase gene knockout pigs. Cloning Stem Cells, 2004, 6: 327-331.

7. Ramsoondar J., Machaty Z., Costa C., Williams B.L., Fodor W.L., Bondioli K.R. Production of alpha 1,3-galactosyltransferase-knockout cloned pigs expressing human alpha 1,2- fucosyltransferase. Biol. Reprod., 2003, 69: 437-445.

8. Lai L., Kolber-Simonds D., Park K.W., Cheong H.T., Greenstein J.L., Im G.S., Samuel M., Bonk A., Rieke A., Day B.N., Murphy C.N., Carter D.B., Hawley R.J., Prather R.S. Production of alpha-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning. Science, 2002, 295(5557): 1089-1092.

9. Dai Y., Vaught T.D., Boone J., Chen S.H., Phelps C.J., Ball S., Monahan J.A., Jobst P.M., McCreath K.J., Lamborn A.E., Cowell-Lucero J.L., Wells K.D., Colman A., Polejaeva I.A., Ayares D.L. Targeted disruption of the alpha1,3-galactosyltransferase gene in cloned pigs. Nat. Biotechnol., 2002, 20(3): 251-255.

10. Sharma A., Naziruddin B., Cui C., Martin M.J., Xu H., Wan H., Lei Y., Harrison C., Yin J., Okabe J., Mathews C., Stark A., Adams C.S., Houtz J., Wiseman B.S., Byrne G.W., Logan J.S. Pig cells that lack the gene for alpha 1-3 galactosyltransferase express low levels of the gal antigen. Transplantation, 2003, 75: 430-436.

11. Jin D.I., Lee S.H., Choi J.H., Lee J.S., Lee J.E., Park K.W., Seo J.S. Targeting effciency of α -1,3-galactosyl transferase gene in pig fetal ?broblast cells. Exp. Mol. Med., 2003, 35: 572-577.

12. Takahagi Y., Fujimura T., Miyagawa S., Nagashima H., Shigehisa T., Shirakura R., Murakami H. Production of alpha 1,3-galactosyltransferase gene knockout pigs expressing both human decay-accelerating factor and N-acetylglucosaminyltransferase III. Mol. Reprod. Dev., 2005, 71: 331-338.

13. Fujimura T, Takahagi Y, Shigehisa T, Nagashima H, Miyagawa S, Shirakura R, Murakami H. Production of alpha 1,3-galactosyltransferase gene-deficient pigs by somatic cell nuclear transfer: a novel selection method for gal alpha 1,3-Gal antigen-deficient cells. Mol. Reprod. Dev., 2008, 75(9): 1372-1378.

14. Shimatsu Y., Yamada K., Horii W., Hirakata A., Sakamoto Y., Waki S., Sano J., Saitoh T., Sahara H., Shimizu A., Yazawa H., Sachs D.H., Nunoya T. Production of cloned NIBS (Nippon Institute for Biological Science) and α -1, 3-galactosyltransferase knockout MGH miniature pigs by somatic cell nuclear transfer using the NIBS breed as surrogates. Xenotransplantation, 2013, 20(3): 157-64.

15. Xin J., Yang H., Fan N., Zhao B., Ouyang Z., Liu Z., Zhao Y., Li X., Song J., Yang Y., Zou Q., Yan Q., Zeng Y., Lai L. Highly efficient generation of GGTA1 biallelic knockout inbred mini-pigs with TALENs. PLoS ONE, 2013, 8(12): e84250.

16. Phelps C.J., Koike C., Vaught T.D., Boone J., Wells K.D., Chen S.H., Ball S., Specht S.M., Polejaeva I.A., Monahan J.A., Jobst P.M., Sharma S.B., Lamborn A.E., Garst A.S., Moore M., Demetris A.J., Rudert W.A., Bottino R., Bertera S., Trucco M., Starzl T.E., Dai Y., Ayares D.L. Production of alpha 1,3-galactosyltransferase-deficient pigs. Science, 2003, 299(5605): 411-414.

17. Kolber-Simonds D., Lai L., Watt S.R., Denaro M., Arn S., Augenstein M.L., Betthauser J., Carter D.B., Greenstein J.L., Hao Y., Im G.S., Liu Z., Mell G.D., Murphy C.N., Park K.W., Rieke A., Ryan D.J., Sachs D.H., Forsberg E.J., Prather R.S., Hawley R.J. Production of alpha-1,3-galactosyltrans-ferase null pigs by means of nuclear transfer with fibroblasts bearing loss of heterozygosity mutations. PNAS USA, 2004, 101(19): 7335-7340.

18. Nottle M.B., Beebe L.F., Harrison S.J., McIlfatrick S.M., Ashman R.J., O'Connell P.J., Salvaris E.J., Fisicaro N., Pommey S., Cowan P.J., d'Apice A.J. Production of homozygous alpha-1,3-galactosyltransferase knockout pigs by breeding and somatic cell nuclear transfer. Xenotransplantation, 2007, 14(4): 339-344.

19. Baehr A. (Re)producing transgenic pigs for xenotransplantation — selection of founder animals and establishment of breeding herds. Inaugural Dissertation zur Erlangung der tiermedizinischen 49 Doktorwurde der Tierarztlichen Fakultat der Ludwig-Maximilians-Universitat Munchen. Muenchen, Germany, 2011.

20. Hauschild J., Petersen B., Santiago Y., Queisser A.-L., Carnwath J.W., Lucas-Hahn A., Zhang L., Meng X., Gregory P.D., Schwinzer R., Cost G.J., Niemann H. Efficient generation of a biallelic knockout in pigs using zinc-finger nucleases. PNAS USA, 2011, 108(29): 12013-12017.

21. Denner J., Tonjes R.R. Infection barriers to successful xenotransplantation focusing on porcine endogenous retroviruses. Clin. Microbiol. Rev., 2012, 25(2): 318-343. CrossRef

22. Luo Y., Lin L., Bolund L., Jensen T.G., Sorensen C.B. Genetically modified pigs for biomedical research. J. Inherit. Metab. Dis., 2012, 35(4): 695-713.

23. d'Apice A.J., Cowan P.J. Xenotransplantation: The next generation of engineered animals. Transpl. Immunol., 2009, 21: 111-115.

24. Weiss E.H., Lilienfeld B.G., Muller S., Muller E., Herbach N., Kealer B., Wanke R., Schwinzer R., Seebach J.D., Wolf E., Brem G. HLA-E/human beta2-microglobulin transgenic pigs: Protection against xenogeneic human anti-pig natural killer cell cytotoxicity. Transplantation, 2009, 87: 35-43.

25. Andreeva T.M. Social'nye aspekty zdorov'ya naseleniya, 2010, 4(16) (http://vestnik.mednet.ru/content/view/234/30/lang,ru/).

26. Vandeput J., Nelissen M., Tanner J.C., Boswick J. A review of skin meshers. Burns, 1995, 21: 364-370. CrossRef

27. Lari A.R., Gang R.K. Expansion technique for skin grafts (Meek technique) in the treatment of severely burned patients. Burns, 2001, 27: 61-66. CrossRef

28. Orgill D.P. Excision and skin grafting of thermal burns. N. Engl. J. Med., 2009, 360: 893-901. CrossRef

29. Sullivan T.P., Eaglstein W.H., Davis S.C., Mertz P. The pig as a model for human wound healing. Wound Repair Regen., 2001, 9: 66-76. CrossRef

30. Harunari N., Zhu K.Q., Armendariz R.T. Deubner H., Muangman P., Carrougher G.G.J., Isik F.F., Gibran N.S., Engrav L.H. Histology of the thick scar on the female, red Duroc pig: final similarities to human hypertrophic scar. Burns , 2006, 32: 669-677. CrossRef

31. Schechter I. Prolonged retention of glutaraldehyde-treated skin allografts and xenografts: immunological and histological studies. Ann. Surg., 1975, 182: 699-704. CrossRef

32. Galili U., Shohet S.B., Kobrin E., Stults C.L., Macher B.A. Man, apes, and old world monkeys differ from other mammals in the expression of alpha-galactosyl epitopes on nucleated cells. J. Biol. Chem., 1988, 263: 17755-17762.

33. Galili U., Wang L., Latemple D.C., Radic M.Z. The natural anti-Gal antibody. Subcell Biochem., 1999, 32: 79-106. CrossRef

34. Weiner J., Yamada K., Ishikawa Y., Moran S., Etter J., Shimizu A., Smith R.N., Sachs D.H. Prolonged survival of GalT-KO swine skin on baboons. Xenotransplantation, 2010, 17(2): 147-152. CrossRef

35. Hilfiker A., Ramm R., Goecke T., Haverich A. Heart valve transplantation: the urgent need for non-immunogenic porcine heart valve matrices. Xenotransplantation, 2013, 20(1): 56. CrossRef

36. Konakci K.Z., Bohle B., Blumer R., Hoetzenecker W., Roth G., Moser B., Boltz-Nitulescu G., Gorlitzer M., Klepetko W., Wolner E., Ankersmit H.J. Alpha-Gal on bioprostheses: xenograft immune response in cardiac surgery. Eur. J. Clin. Invest., 2005, 35(1): 17-23.

37. Kasimir M.T., Reider E., Seebacher G., Wolner E., Weigel G., Simon P. Presence and elimination of the xenoantigen gal(alpha1,3) gal in tissue-engineered heart valves. Tissue Eng., 2005, 11(7-8): 1274-1280.

38. Lila N., McGregor C.G., Carpentier S., Rancic J., Byrne G.W., Carpentier A. Gal knockout pig pericardium: new source of material for heart valve bioprostheses. J. Heart Lung Transplant., 2010, 29(5): 538-543. CrossRef

39. Kobayashi T., Yamaguchi T., Hamanaka S., Kato-Itoh, M., Yamazaki Y., Ibata M., Sato H., Lee Y.S., Usui J., Knisely A.S., Hirabayashi M., Nakauchi H. Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell, 2010, 142(5): 787-799. CrossRef

40. Usui J., Kobayashi T., Yamaguchi T., Knisely S., Nishinakamura R., Nakauchi H. Generation of kidney from pluripotent stem cells via blastocyst complementation. Am. J. Pathol., 2012, 180(6): 2417-2426. CrossRef

41. Matsunari H., Nagashima H., Watanabe M., Umeyama K., Nakano K., Nagaya M., Kobayashi T., Yamaguchi T., Sumazaki R., Herzenberg L.A.,Nakauchi H. Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs. PNAS USA, 2013, 110 (12), 4557-4562. CrossRef

42. Nakano K., Watanabe M., Matsunari H., Matsuda T., Honda K., Maehara M., Kanai T., Hayashida G., Kobayashi M., Kuramoto M., Arai Y., Umeyama K., Fujishiro S.H., Mizukami Y., Nagaya M., Hanazono Y., Nagashima H. Generating porcine chimeras using inner cell mass cells and parthenogenetic preimplantation embryos. PloS ONE, 2013, 8(4): e61900.

43. Eckardt S., McLaughlin, K.J., Willenbring H. Mouse chimeras as a system to investigate development, cell and tissue function, disease mechanisms and organ regeneration. Cell Cycle, 2011, 10(13): 2091-2099.

back