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Reporter mice and drug discovery and development

Nature Reviews Drug Discovery volume 4, pages 249–255 (2005)Cite this article

Abstract

In vivo reporter gene and imaging technologies have the potential to contribute to the drug discovery pipeline in several areas. They provide systems that enable the study of the biochemical activity of a target in disease, and in response to a drug, to be monitored over periods of time, and offer more accurate methods of measuring pharmacodynamics and toxicity. Although reporter-gene technology is in its infancy, with further refinement reporter animals could become a valuable tool in the early stages of target and lead identification and preclinical drug development.

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Figure 1: Strategies for the generation of reporter animals for drug development.
Figure 2: Reporter mice: a revolution in drug discovery and development.

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References

  1. Gershell, L. J. & Atkins, J. H. A brief history of novel drug discovery technologies. Nature Rev. Drug Discov. 2, 321–327 (2003).

    Article  CAS  Google Scholar 

  2. Zambrowicz, B. P. & Sands, A. T. Knockouts model the 100 best-selling drugs — will they model the next 100? Nature Rev. Drug Discov. 2, 38–51 (2003).

    Article  CAS  Google Scholar 

  3. Knowles, J. & Gromo, G. A guide to drug discovery: target selection in drug discovery. Nature Rev. Drug Discov. 2, 63–69 (2003)

    Article  CAS  Google Scholar 

  4. Wang, Y., DeMayo, F. J., Tsai, S. Y. & O'Malley, B. W. Ligand-inducible and liver-specific target gene expression in transgenic mice. Nature Biotechnol. 15, 239–243 (1997).

    Article  CAS  Google Scholar 

  5. Solomin, L. et al. Retinoid-X receptor signalling in the developing spinal cord. Nature 395, 398–402 (1998).

    Article  CAS  Google Scholar 

  6. Mata De Urquiza, A., Solomin, L. & Perlmann, T. Feedback-inducible nuclear-receptor-driven reporter gene expression in transgenic mice. Proc. Natl Acad. Sci. USA 96, 13270–13275 (1999).

    Article  CAS  Google Scholar 

  7. Ciana, P. et al. Engineering of a mouse for the in vivo profiling of estrogen receptor activity. Mol. Endocrinol. 15, 1104–1113 (2001).

    Article  CAS  Google Scholar 

  8. Nagel, S. C., Hagelbarger, J. L. & McDonnell, D. P. Development of an ER action indicator mouse for the study of estrogens, selective ER modulators (SERMs), and xenobiotics. Endocrinology 142, 4721–4728 (2001).

    Article  CAS  Google Scholar 

  9. Rossant, J., Zirngibl, R., Cado, D., Shago, M. & Giguere, V. Expression of a retinoic acid response element-hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis. Genes Dev. 5, 1333–1344 (1991).

    Article  CAS  Google Scholar 

  10. Montoliu, L., Blendy, J. A., Cole, T. J. & Schutz, G. Analysis of perinatal gene expression: hormone response elements mediate activation of a lacZ reporter gene in liver of transgenic mice. Proc. Natl Acad. Sci. USA 92, 4244–4248 (1995).

    Article  CAS  Google Scholar 

  11. Ciana, P. et al. In vivo imaging of transcriptionally active estrogen receptors. Nature Med. 9, 82–86 (2003).

    Article  CAS  Google Scholar 

  12. Fukumura, D. et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 94, 715–725 (1998).

    Article  CAS  Google Scholar 

  13. Lyons, S. K., Meuwissen, R., Krimpenfort, P. & Berns A. The generation of a conditional reporter that enables bioluminescence imaging of Cre/loxP-dependent tumorigenesis in mice. Cancer Res. 63, 7042–7046 (2003).

    CAS  PubMed  Google Scholar 

  14. Yamaguchi, M., Saito, H., Suzuki, M. & Mori, K. Visualization of neurogenesis in the central nervous system using nestin promoter-GFP transgenic mice. Neurorep. 11, 1991–1996 (2000).

    Article  CAS  Google Scholar 

  15. Schmidt-Ullrich, R. et al. NF-κB activity in transgenic mice: developmental regulation and tissue specificity. Development 122, 2117–2128 (1996).

    CAS  PubMed  Google Scholar 

  16. Carlsen, H., Moskaug, J. O., Fromm, S. H. & Blomhoff, R. In vivo imaging of NF-κB activity. J. Immunol. 168, 1441–1446 (2002).

    Article  CAS  Google Scholar 

  17. Huang, C. et al. Blocking activator protein-1 activity, but not activating retinoic acid response element, is required for the antitumor promotion effect of retinoic acid. Proc. Natl Acad. Sci. USA 94, 5826–5830 (1997).

    Article  CAS  Google Scholar 

  18. Bruning, J. C. et al. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 88, 561–572 (1997).

    Article  CAS  Google Scholar 

  19. Su, L. -K. et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668–670 (1992).

    Article  CAS  Google Scholar 

  20. DiMasi, J. A., Hansen, R. W. & Grabowski, H. G. The price of innovation: new estimates of drug development costs. J. Health Econ. 22, 151–185 (2003).

    Article  Google Scholar 

  21. Preziosi, P. Science, pharmacoeconomics and ethics in drug R&D: a sustainable future scenario? Nature Rev. Drug Discov. 3, 521–526 (2004).

    Article  CAS  Google Scholar 

  22. Geiling, E. M. K. & Cannon, P. R. Pathologic effects of elixir of sulphanilamide (diethylene glicol) poisoning. JAMA 111, 919–926 (1938).

    Article  CAS  Google Scholar 

  23. Rawlins, M. D. Cutting the cost of drug development? Nature Rev. Drug Discov. 3, 360–364 (2004).

    Article  CAS  Google Scholar 

  24. Freireich, E. J., Gehan, E. A., Rall, D. P., Schmidt, L. H. & Skipper, H. E. Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother. Rep. 50, 219–244 (1966).

    CAS  PubMed  Google Scholar 

  25. Xie, W. & Evans, R. M. Pharmaceutical use of mouse models humanized for the xenobiotic receptor. Drug Discov. Today 7, 509–515 (2002).

    Article  CAS  Google Scholar 

  26. Kenakin, T. Predicting therapeutic value in the lead optimization phase of drug discovery. Nature Rev. Drug Discov. 2, 429–438 (2003).

    Article  CAS  Google Scholar 

  27. Verkhusha, V. V. & Lukyanov, K. A. The molecular properties and applications of Anthozoa fluorescent proteins and chromoproteins. Nature Biotechnol. 22, 289–296 (2004).

    Article  CAS  Google Scholar 

  28. Dmitriy, M. et al. Kindling fluorescent proteins for precise in vivo photolabeling. Nature Biotechnol. 21, 191–194 (2003).

    Article  Google Scholar 

  29. Paulmurugan, R. et al. Noninvasive imaging of protein-protein interactions in living subjects by using reporter protein complementation and reconstitution strategies. Proc. Natl Acad. Sci. USA 99, 15608–15613 (2002).

    Article  CAS  Google Scholar 

  30. Willard, F. S. et al. Fluorescence-based assays for RGS box function. Methods Enzymo. 389, 56–71 (2004).

    Article  CAS  Google Scholar 

  31. Ray, P. et al. Noninvasive quantitative imaging of protein–protein interactions in living subjects. Proc. Natl Acad. Sci. USA 99, 3105–3110 (2002).

    Article  CAS  Google Scholar 

  32. Massoud, T. F. & Gambhir, S. S. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev. 17, 545–580 (2003).

    Article  CAS  Google Scholar 

  33. Contag, C. H. & Bachmann, M. H. Advances in in vivo bioluminescence imaging of gene expression. Annu. Rev. Biomed. Eng. 4, 235–60 (2002).

    Article  CAS  Google Scholar 

  34. Hadjantonakis, A. K., Dickinson, M. E., Fraser, S. E. & Papaioannou, V. E. Technicolour transgenics: imaging tools for functional genomics in the mouse. Nature Rev. Genet. 4, 613–625 (2003).

    Article  CAS  Google Scholar 

  35. Louie, A. Y. et al. In vivo visualization of gene expression using magnetic resonance imaging. Nature Biotechnol. 18, 321–325 (2000).

    Article  CAS  Google Scholar 

  36. Moore, A. et al. Human transferrin receptor gene as a marker gene for MR imaging. Radiology. 221, 244–250 (2001).

    Article  CAS  Google Scholar 

  37. Liang, Q. et al. Noninvasive imaging of reporter gene expression in living subjects. Adv. Cancer Res. 92, 29–80 (2004).

    Article  Google Scholar 

  38. Rudin, M. & Weissleder, R. Molecular imaging in drug discovery and development. Nature Rev. Drug Discov. 2, 123–131 (2003).

    Article  CAS  Google Scholar 

  39. Di Lorenzo, D. et al. Isomer specific activity of DDT with estrogen receptor in adult and sucling mice. Endocrinology 143, 4544–4551 (2002).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacological Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti 9, Milan, 20133, Italy

    Adriana Maggi & Paolo Ciana

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  1. Adriana Maggi
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  2. Paolo Ciana
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Correspondence to Adriana Maggi.

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The authors declare no competing financial interests.

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Maggi, A., Ciana, P. Reporter mice and drug discovery and development. Nat Rev Drug Discov 4, 249–255 (2005). https://doi.org/10.1038/nrd1661

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