the use of transgenic animals in drug research

2
ELSEVIER European Journal of Pharmaceutical Sciences 2 (1994) 22-23 EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES The use of transgenic animals in drug research Bernward Garthoff Bayer AG, PF Center Monheim, 51368 Leverkusen, Germany Superficially, it might appear to be a contradic- tion in itself to limit the use of animals by using transgenic animals. However, closer examination of this issue demonstrates that transgenic technol- ogy can lead to a reduction, for example, in the use of larger animals and especially of primates. Alternative methodology to animal experimenta- tion is not only limited to total replacement, it also means application of refinement and reduc- tion, the other two of the three 'Rs'. To some extent, this is the better and more rapid way to achieve a lot in limiting the total number of animals used to attain specific scientific objec- tives. Transgenic animals offer one major advan- tage: they represent the ideal model of testing for efficacy or for assessing risks in that they may reflect the human situation the closest. This means fewer animals per dose, a few animals only for the whole testing purpose, as the results are optimal and adapted to the needs of testing. In that regard, use of transgenic animals compares well with the refined LDs0 acute toxici- ty testing nowadays. Transgenic animals are animals that carry new genes, preferably human diseased ones. These genes are usually inserted by microinjection of purified DNA into the pronucleus of a fertilized egg. The new genetic material becomes inte- grated into the chromosomal DNA of the host organism, and transmitted as a heritable trait to succeeding generations of progeny. These so- called 'transgenes' (theoretically derived from any species imaginable) can be efficiently ex- pressed, with the tissue distribution of expression determined by discrete elements close to the gene coding sequence. Transgenic mice and rats underscore the im- measurable value of research involving the intact organism for obtaining subtle information in crucial areas. Examples are the creation of novel rodent models for studying human disease and therapies substituting for models that previously existed only in larger animals, such as chimpan- 0928-0987/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSD1 0928-0987(94)00021-Q zees for hepatitis B studies. Chimpanzees were also considered one of the most representative AIDS models. Although mice that express HIV genes clearly do not develop AIDS, they do exhibit some disorders, e.g. skin lesions that closely resemble Kaposi's sarcoma, highly charac- teristic of AIDS-related diseases. In terms of vaccine testing, fewer primates might also be used by producing transgenic mice for testing poliovirus type 3 neurovirulence. Transgenic animals are not only developed for investigation of disease pathogenesis or viral vaccine testing, but also for therapeutic interven- tion in disorders such as diabetes, cancer, or cardiovascular, infectious and central nervous diseases (e.g. Alzheimer's). The area of athero- sclerosis might serve as an example: A new pharmacological model is created by the incorpo- ration of novel genes into genomes normally lacking them, such as the human cholesterol ester transfer protein gene in mice whose expression causes the development of human-like lipopro- tein profiles. This mouse model is proposed as a new, specific approach for atherosclerosis re- search including the testing of CETP-inhibiting drugs. It is, therefore, also commercially avail- able from a breeder company now. Another example is a new mouse model of atherosclerosis in which expression of human apolipoprotein(a) -- high levels are associated with increased risk of atherosclerosis in humans--causes a high rate of 'fatty streak' formation in the aortas and thereby offers a chance to find curative therapies. Transgenic animals are and will also be pro- duced that are extra sensitive to toxicity of drugs and/or their metabolites, thereby streamlining the efficiency of the animal testing phase of new drugs. In conclusion, although the development of transgenic animals appears to be a kind of addi- tional creation of laboratory animals, it has the potential of limiting the total number of animals

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Page 1: The use of transgenic animals in drug research

ELSEVIER European Journal of Pharmaceutical Sciences 2 (1994) 22-23

E U R O P E A N J O U R N A L OF

PHARMACEUTICAL SCIENCES

The use of transgenic animals in drug research

Bernward Garthoff

Bayer AG, PF Center Monheim, 51368 Leverkusen, Germany

Superficially, it might appear to be a contradic- tion in itself to limit the use of animals by using transgenic animals. However, closer examination of this issue demonstrates that transgenic technol- ogy can lead to a reduction, for example, in the use of larger animals and especially of primates. Alternative methodology to animal experimenta- tion is not only limited to total replacement, it also means application of refinement and reduc- tion, the other two of the three 'Rs'. To some extent, this is the better and more rapid way to achieve a lot in limiting the total number of animals used to attain specific scientific objec- tives. Transgenic animals offer one major advan- tage: they represent the ideal model of testing for efficacy or for assessing risks in that they may reflect the human situation the closest.

This means fewer animals per dose, a few animals only for the whole testing purpose, as the results are optimal and adapted to the needs of testing. In that regard, use of transgenic animals compares well with the refined LDs0 acute toxici- ty testing nowadays.

Transgenic animals are animals that carry new genes, preferably human diseased ones. These genes are usually inserted by microinjection of purified D N A into the pronucleus of a fertilized egg. The new genetic material becomes inte- grated into the chromosomal DNA of the host organism, and transmitted as a heritable trait to succeeding generations of progeny. These so- called ' transgenes' (theoretically derived from any species imaginable) can be efficiently ex- pressed, with the tissue distribution of expression de termined by discrete elements close to the gene coding sequence.

Transgenic mice and rats underscore the im- measurable value of research involving the intact organism for obtaining subtle information in crucial areas. Examples are the creation of novel rodent models for studying human disease and therapies substituting for models that previously existed only in larger animals, such as chimpan-

0928-0987/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSD1 0928-0987(94)00021-Q

zees for hepatitis B studies. Chimpanzees were also considered one of the most representative AIDS models. Al though mice that express HIV genes clearly do not develop AIDS, they do exhibit some disorders, e.g. skin lesions that closely resemble Kaposi's sarcoma, highly charac- teristic of AIDS-related diseases. In terms of vaccine testing, fewer primates might also be used by producing transgenic mice for testing poliovirus type 3 neurovirulence.

Transgenic animals are not only developed for investigation of disease pathogenesis or viral vaccine testing, but also for therapeutic interven- tion in disorders such as diabetes, cancer, or cardiovascular, infectious and central nervous diseases (e.g. Alzheimer's). The area of athero- sclerosis might serve as an example: A new pharmacological model is created by the incorpo- ration of novel genes into genomes normally lacking them, such as the human cholesterol ester transfer protein gene in mice whose expression causes the development of human-like lipopro- tein profiles. This mouse model is proposed as a new, specific approach for atherosclerosis re- search including the testing of CETP-inhibit ing drugs. It is, therefore, also commercially avail- able from a breeder company now.

Another example is a new mouse model of atherosclerosis in which expression of human apolipoprotein(a) - - high levels are associated with increased risk of atherosclerosis in h u m a n s - - c a u s e s a high rate of 'fatty streak' formation in the aortas and thereby offers a chance to find curative therapies.

Transgenic animals are and will also be pro- duced that are extra sensitive to toxicity of drugs and /o r their metabolites, thereby streamlining the efficiency of the animal testing phase of new drugs.

In conclusion, although the development of transgenic animals appears to be a kind of addi- tional creation of laboratory animals, it has the potential of limiting the total number of animals

Page 2: The use of transgenic animals in drug research

B. Garthoff / European Journal of Pharmaceutical Sciences 2 (1994) 22-23 23

used as its net effect. As all of us have to accept that basic research into human diseases and especially the testing of potential new thera- peutics has to be checked in an intact in vivo organism (e.g. before been given to man), the existence of transgenics is a step forward and their further deve lopment deserves our support .

References

Harris et al. (1993) Transgenic animals in drug develop- ment. Agents Actions 38, Spec. Conf. Issue, C57-C58.

Lathe, R. and Mullins, J.J. (1993) Transgenic animals as models for human disease--report of an EC Study Group. Transgenic Res. 2, 286-299.

Liggitt, H.D. et al. (1992) Potential applications of trans- genic animals in drug development. In: Gibbson, G.G. (Ed.) Progress in Drug Metabolism, Vol. 13. Taylor & Francis, London, pp. 1-33.

Merlino, G.T. (1991) Transgenic animals in biomedical research. FASEB J. 5, 2996-3001.

Dragunsky, E. et al. (1993) Transgenic PVR Tg-1 mice for testing of polivirus type 3 neurovirulence: comparison with monkey test. Biologicals 21, 233-237.