General topic: applications of transgenic rabbits in biomedical research - based on literature search

S. Zhao, K. Wei, Q. Yu, Y. Li, F. Cheg, Y. Wang, P. Yang, J. Fan, E. Liu


Transgenic rabbits are widely used as a model organism for biomedical research, and the transgenic rabbit system is especially valuable because it fills an important niche between laboratory mice and larger domesticated mammals. In order to describe the current status and development trends of the use of transgenic rabbits in biomedical research precisely, we performed a quantitative analysis of the published data, collected by searching biomedical databases. Currently, there are about 217 papers related to transgenic rabbits, originating from 22 countries. The number of publications has slowly increased over time, reaching its peak in 2004 and 2007. Approximately one third of the publications come from the USA, and one quarter come from Japan. The USA, Japan and France were the top three producers of publications related to transgenic rabbits. These publications mainly focused on cardiovascular disease (CVD) and the study of therapeutic protein bioreactors. Approximately 19 transgenic rabbit lines have been established for the study of CVD, and 20 recombinant proteins have been produced from transgenic rabbit milk or blood. The remaining publications largely focused on virology and immunology, diabetes mellitus, cancer, and genetics. These publications provide new insights into the mechanisms responsible for the development of human disease and shed light on the management of some genetic disorders. Thus, this quantitative review of the literature reveals that transgenic rabbits play an increasingly important role in biomedical research.


transgenic rabbits; biomedical research; atherosclerosis; bioreactor

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Araki M., Fan J., Challah M., Bensadoun A., Yamada N., Honda K., Watanabe T. 2000. Transgenic rabbits expressing human lipoprotein lipase. Cytotechnology, 33: 93-99.

Baranyi M., Hiripi L., Szabó L., Catunda A.P., Harsányi I., Komáromy P., Bosze Z. 2007. Isolation and some effects of functional, lowphenylalanine kappa-casein expressed in the milk of transgenic rabbits. J Biotechnol., 128: 383-392.

Bijvoet A.G., Van Hirtum H., Kroos M.A., Van de Kamp E.H., Schoneveld O., Visser P., Brakenhoff J.P., Weggeman M., van Corven E.J., Van der Ploeg A.T., Reuser A.J. 1999. Human acid alpha-glucosidase from rabbit milk has therapeutic effect in mice with glycogen storage disease type II. Hum. Mol. Genet., 8: 2145- 2153.

Bodrogi L., Brands R., Raaben W., Seinen W., Baranyi M., Fiechter D., Bosze Z. 2006. High level expression of tissue-nonspecific alkaline phosphatase in the milk of transgenic rabbits. Transgenic Res., 15: 627-636.

Bosze Z., Hiripi L., Carnwath J.W., Niemann H. 2003. The transgenic rabbit as model for human diseases and as a source of biologically active recombinant proteins. Transgenic Res., 12: 541-553.

Bosze Z., Houdebine L.M. 2006. Application of rabbits in biomedical research: A review. World Rabbit Sci., 14: 1-14.

Brem G., Besenfelder U., Zinovieva N., Seregi J., Solti L., Hartl P. 1995. Mammary gland-specific expression of chymosin constructs in transgenic rabbits. Theriogenology., 43: 175.

Brem G., Hartl P., Besenfelder U., Wolf E., Zinovieva N., Pfaller R. 1994. Expression of synthetic cDNA sequences encoding human insulin-like growth factor-1 (IGF-1) in the mammary gland of transgenic rabbits. Gene., 149:351-355.

Brousseau M.E., Hoeg J.M. 1999. Transgenic rabbits as models for atherosclerosis research. J. Lipid Res., 40: 365-375.

Brunner M., Peng X., Liu G.X., Ren X.Q., Ziv O., Choi B.R., Mathur R., Hajjiri M., Odening K.E., Steinberg E., Folco E.J., Pringa E., Centracchio J., Macharzina R.R., Donahay T., Schofield L., Rana N., Kirk M., Mitchell G.F., Poppas A., Zehender M., Koren G. 2008. Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome. J. Clin. Invest., 118: 2246-2259.

Buhler T.A., Bruyere T., Went D.F., Stranzinger G., Burki K. 1990. Rabbit beta-casein promoter directs secretion of human interleukin-2 into the milk of transgenic rabbits. Bio-Technol., 8: 140-143.

Chrenek P., Ryban L., Vetr H., Makarevich A.V., Uhrin P., Paleyanda R.K., Binder B.R. 2007. Expression of recombinant human factor VIII in milk of several generations of transgenic rabbits. Transgenic Res., 16: 353-361.

Coulibaly S., Besenfelder U., Fleischmann M., Zinovieva N., Grossmann A., Wozny M., Bartke I., Togel M., Muller M., Brem G. 1999. Human nerve growth factor beta (hNGF-beta): mammary gland specific expression and production in transgenic rabbits. FEBS Lett., 444:111-116.

Dragin S., Chrastinova L., Makarevich A., Chrenek P. 2005. Production of recombinant human protein C in the milk of transgenic rabbits from the F3 generation. Folia Biol. (Krakow)., 53: 129-132.

Duverger N., Viglietta C., Berthou L., Emmanuel F., Tailleux A., Parmentier-Nihoul L., Laine B., Fievet C., Castro G.., Fruchart J.C., Houbebine L.M., Denefie P. 1996b. Transgenic rabbits expressing human apolipoprotein A-I in the liver. Arterioscl. Throm. Vasc., 16: 1424-1429.

Duverger, N., Kruth, H., Emmanuel, F., Caillaud, J. M., Viglietta, C., Castro, G., Tailleux, A., Fievet, C., Fruchart, J. C., Houdebine, L.M., Denefle, P. 1996. Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits. Circulation, 94: 713-717.

Ebbert J.O., Dupras D.M., Erwin P.J. 2003. Searching the medical literature using PubMed: a tutorial. Mayo Clin. Proc., 78: 87-91.

Fan J., Wang J., Bensadoun A., Lauer S.J., Dang Q., Mahley R.W., Taylor J.M. 1994. Overexpression of hepatic lipase in transgenic rabbits leads to a marked reduction of plasma high density lipoproteins and intermediate density lipoproteins. Proc. Natl. Acad. Sci. U. S. A., 91: 8724-8728.

Fan J., McCormick S.P., Krauss R.M., Taylor S., Quan R., Taylor J.M., Young S.G. 1995. Overexpression of human apolipoprotein B-100 in transgenic rabbits results in increased levels of LDL and decreased levels of HDL. Arterioscl. Throm.Vasc., 15: 1889-1899.

Fan J., Ji Z., Huang Y., de Silva H., Sanan D., Mahley R.W., Innerarity T.L., Taylor J.M. 1998. Increased expression of apolipoprotein E in transgenic rabbits results in reduced levels of very low density lipoproteins and an accumulation of low density lipoproteins in plasma. J Clin. Invest., 101: 2151-2164.

Fan J., Araki M., Wu L., Challah M., Shimoyamada H., Lawn R.M., Kakuta H., Shikama H., Watanabe T. 1999a. Assembly of lipoprotein (a) in transgenic rabbits expressing human apolipoprotein (a). Biochem. Biophys. Res. Commun., 255: 639-644.

Fan J., Challah M., Watanabe T. 1999b. Transgenic rabbit models for biomedical research: current status, basic methods and future perspectives. Pathol. Int., 49: 583-594.

Fan J., Watanabe T. 2003. Transgenic rabbits as therapeutic protein bioreactors and human disease models. Pharmacol. Therapeut., 99: 261-282.

Fan J., Wang X., Wu L., Matsumoto S.I., Liang J., Koike T., Ichikawa T., Sun H., Shikama H., Sasaguri Y., Watanabe T. 2004. Macrophagespecific overexpression of human matrix metalloproteinase-12 in transgenic rabbits. Transgenic Res., 13: 261-269.

Galet C., Le Bourhis C.M., Chopineau M., Le Griec G., Perrin A., Magallon T., Attal J., Viglietta C., Houdebine L.M., Guillou F. 2000. Expression of a single betaalpha chain protein of equine LH/ CG in milk of transgenic rabbits and its biological activity. Mol. Cell. Endocrinol., 174: 31-40.

Graur D., Duret L., Gouy M. 1996. Phylogenetic position of the order Lagomorpha (rabbits, hares and allies). Nature, 379: 333-335.

Hammer R.E., Pursel V.G., Rexroad C.E., Wall R.J., Bolt D.J., Ebert K.M., Palmiter R.D., Brinster R.L. 1985. Production of transgenic rabbits, sheep and pigs by microinjection. Nature, 315:680-683.

Hiripi L., Makovics F., Halter R., Baranyi M., Paul D., Carnwath J.W., Bösze Z., Niemann H. 2003. Expression of active human blood clotting factor VIII in mammary gland of transgenic rabbits. DNA Cell. Biol., 22: 41-45.

Hoeg J.M., Santamarina-Fojo S., Berard A.M., Cornhill J.F., Herderick E.E., Feldman S.H., Haudenschild C.C., Vaisman B.L., Hoyt R.F., Demosky S.J., Kauffman R.D., Hazel C.M., Marcovina S.M., Brewer H.B. 1996. Overexpression of lecithin:cholesterol acyltransferase in transgenic rabbits prevents diet-induced atherosclerosis. Proc. Natl. Acad. Sci. U. S. A., 93: 11448-11453.

Houdebine L.M., Fan J. 2009. Rabbit Biotechnology: Rabbit genomics, transgenesis, cloning and models. Springer Dordrecht Heidelberg London New York

Huang Y.D., Schwendner S.W., Rall S.C., Sanan D.A., Mahley R.W. 1997. Apolipoprotein E2 transgenic rabbits - Modulation of the type III hyperlipoproteinemic phenotype by estrogen and occurrence of spontaneous atherosclerosis. J. Biol. Chem., 272: 22685-22694.

James J., Sanbe A., Yager K., Martin L., Klevitsky R., Robbins J. 2000. Genetic manipulation of the rabbit heart via transgenesis. Circulation, 101: 1715-1721.

James J., Zhang Y., Wright K., Witt S., Glascock E., Osinska H., Klevitsky R., Martin L., Yager K., Sanbe A., Robbins J. 2002. Transgenic rabbits expressing mutant essential light chain do not develop hypertrophic cardiomyopathy. J. Mol. Cell. Cardiol., 34: 873-882.

Kavinsky C.J., Umeda P.K., Levin J.E., Sinha A.M., Nigro J.M., Jakovcic S., Rabinowitz M. 1984. Analysis of cloned mRNA sequences encoding subfragment 2 and part of subfragment 1 of alpha and beta-myosin heavy chains of rabbit heart. J. Biol. Chem., 259: 2775-2781.

Khodarovich IuM., Vorob’eva N.E., Mezina M.N., Piniugina M.V., Prokof’ev M.I., Larionov O.A. 2008. [Expression of humanºinterferon beta in the mammary gland of transgenic rabbits.] Bioorg Khim., 34:185-193.

Kitajima S., Liu E., Morimoto M., Koike T., Yu Y., Watanabe T., Imagawa S., Fan J. 2005. Transgenic rabbits with increased VEGF expression develop hemangiomas in the liver: a new model for Kasabach-Merritt syndrome. Lab. Invest., 85:1517-1527.

Koles K., van Berkel P.H., Pieper F.R., Nuijens J.H., Mannesse M.L., Vliegenthart J.F., Kamerling J.P. 2004. N- and O-glycans of recombinant human C1 inhibitor expressed in the milk of transgenic rabbits. Glycobiology, 14:51-64.

Korhonen V.P., Tolvanen M., Hyttinen J.M., Uusioukari M., Sinervirta R., Alhonen L., Jauhiainen M., Janne O.A., Janne J. 1997. Expression of bovine beta-lactoglobulin human erythropoietin fusion protein in the milk of transgenic mice and rabbits. Eur. J. Biochem., 245: 482-489.

Limonta J.M., Castro F.O., Martinez R., Puentes P., Ramos B., Aguilar A., Lleonart R.L., de la Fuente J. 1995. Transgenic rabbits as bioreactors for the production of human growth hormone. J Biotechnol., 40: 49-58.

Lubon H., Palmer C. 2000. Transgenic animal bioreactors—where we are. Transgenic Res., 9: 301-304.

Marian A.J., Wu Y., Lim D.S., McCluggage M., Youker K., Yu Q.T., Brugada R., DeMayo F., Quinones M., Roberts R. 1999. A transgenic rabbit model for human hypertrophic cardiomyopathy. J Clin. Invest., 104: 1683-1692.

Massoud M., Attal J., Thepot D., Pointu H., Stinnakre M.G., Theron M.C., Lopez C., Houdebine L.M. 1996. The deleterious effects of human erythropoietin gene driven by the rabbit whey acidic protein gene promoter in transgenic rabbits. Reprod. Nutr. Dev., 36: 555- 563.

Massoud M., Bischoff R., Dalemans W., Pointu H., Attal J., Schultz H., Clesse D., Stinnakre M.G., Pavirani A., Houdebine L.M. 1990. Production of human proteins in the blood of transgenic animals. C R Acad Sci Ser III Sci Vie., 311: 275-280.

Massoud M., Bischoff R., Dalemans W., Pointu H., Attal J., Schultz H., Clesse D., Stinnakre M.G., Pavirani A., Houdebine L.M. 1991. Expression of active recombinant human alpha 1-antitrypsin in transgenic rabbits. J. Biotechnol., 18:193-203.

McKee C., Gibson A., Dalrymple M., Emslie L., Garner I., Cottingham I. 1998. Production of biologically active salmon calcitonin in the milk of transgenic rabbits. Nat. Biotechnol., 16: 647-651.

Nishizawa T., Shen Y.T., Rossi F., Hong C., Robbins J., Ishikawa Y., Sadoshima J., Vatner D.E., Vatner S.F. 2007. Altered autonomic control in conscious transgenic rabbits with overexpressed cardiac Gsalpha. Am. J. Physiol.-Heart Circul. Physiol., 292: H971-975.

Pattison J.S., Waggoner J.R., James J., Martin L., Gulick J., Osinska H., Klevitsky R., Kranias E.G., Robbins J. 2008. Phospholamban overexpression in transgenic rabbits. Transgenic Res., 17: 157-170.

Recalde D., Baroukh N., Viglietta C., Prince S., Verona J., Vergnes L., Pidoux J., Nanjee M.N., Brites F., Ochoa A., Castro G., Zakin M.M., Miller N.E., Houdebine L.M. 2004. Human apoA-I/C-III/AIV gene cluster transgenic rabbits: effects of a high-cholesterol diet. FEBS Lett. 572: 294-298.

Reigo E., Limonta J., Aguilar A., Perez A., de Armas R., Solano R., Ramos B., Castro F.O., de la Fuente J. 1993. Production of transgenic mice and rabbits that carry and express the human tissue plasminogen activator cDNA under the control of a bovine alpha S1 casein promoter. Theriogenology, 39: 1173-1185.

Rodriguez A., Castro F.O., Aguilar A., Ramos B., Del Barco D.G., Lleonart R., De la Fuente J. 1995. Expression of active human erythropoietin in the mammary gland of lactating transgenic mice and rabbits. Biol. Res., 28: 141-153.

Rouy D., Duverger N., Lin S.D., Emmanuel F, Houdebine L.M., Denefle P, Viglietta C, Gong E, Rubin E.M., Hughes S.D. 1998. Apolipoprotein(a) yeast artificial chromosome transgenic rabbits. Lipoprotein(a) assembly with human and rabbit apolipoprotein B. J Biol. Chem., 273:1247-1251.

Sanbe A., James J., Tuzcu V., Nas S., Martin L., Gulick J., Osinska H., Sakthivel S., Klevitsky R., Ginsburg K.S., Bers D.M., Zinman B., Lakatta E.G., Robbins J. 2005. Transgenic rabbit model for human troponin I-based hypertrophic cardiomyopathy. Circulation, 111: 2330-2338.

Shen J., Kuhn H., Petho-Shramm A., Chan L. 1995. Transgenic rabbits with the integrated human 15-lipoxygenase gene driven by a lysozyme promoter: macrophage-specific expression and variable positional specificity of the transgenic enzyme. FASEB J., 9:16231631.

Soler E., Le Saux A., Guinut F., Passet B., Cohen R., Merle C., Charpilienne A., Fourgeux C., Sorel V., Piriou A., Schwartz-Cornil I., Cohen J., Houdebine L.M. 2005. Production of two vaccinating recombinant rotavirus proteins in the milk of transgenic rabbits. Transgenic Res., 14: 833-844.

Stromqvist M., Houdebine M., Andersson J.O., Edlund A., Johansson T., Viglietta C., Puissant C., Hansson L. 1997. Recombinant human extracellular superoxide dismutase produced in milk of transgenic rabbits. Transgenic Res., 6: 271-278.

Taylor J.M., Fan J. 1997. Transgenic rabbit models for the study of atherosclerosis. Front. Biosci,. 2: 298-308.

Wolf E., Jehle P.M., Weber M.M., Sauerwein H., Daxenberger A., Breier B.H., Besenfelder U., Frenyo L., Brem G. 1997. Human insulinlike growth factor I (IGF-I) produced in the mammary glands of transgenic rabbits: yield, receptor binding, mitogenic activity, and effects on IGF-binding proteins. Endocrinology, 138: 307-313.

Yamanaka S., Balestra M.E., Ferrell L.D., Fan J., Arnold K.S., Taylor S., Taylor J.M., Innerarity T.L. 1995. Apolipoprotein B mRNAediting protein induces hepatocellular carcinoma and dysplasia in transgenic animals. Proc. Natl. Acad. Sci. U. S. A., 92, 8483-8487.

Zinovieva N., Lassnig C., Schams D., Besenfelder U., Wolf E., Muller S., Frenyo L., Seregi J., Muller M., Brem G. 1998. Stable production of human insulin-like growth factor 1 (IGF-1) in the milk of hemi- and homozygous transgenic rabbits over several generations. Transgenic Res., 7: 437-447.

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