Transgenic animal testing

Animal Species/Model Selection. Safety evaluation should include the use of relevant species, in which the test article is pharmacologically active due, for example, to the expression of the appropriate receptor molecule. These can be screened with in vitro rector binding assays. Safety evaluation should normally include two appropriate species, if possible and/or feasible. The potential utility of gene knockout and/or transgenic animals in safety assessment is discussed. 

Gulezian, D., D. Jacobson-Rram, C.B. McCullough, et al. 2000. Use of transgenic animals for carcinogenicity testing Considerations and implications for risk assessment. Toxicol. Pathol. 28 482 99. 

Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use Points to Consider on Plasmid DNA Vaccines for Preventive Infectious Disease Indications Points to Consider in the Manufacture and Testing of Therapeutic Products for Human Use Derived from Transgenic Animals... 

Another possible system for the production of therapeutic proteins consists of transgenic animals. Although there is controversy regarding safety and reproducibility, many reports on this subject have been published and some proteins derived from these systems are currently under clinical trials. Parker et al. (2004) purified and characterized human fetoprotein a secreted in transgenic goat milk. This protein, used in the treatment of autoimmune diseases, proved to be identical to the native form by mass spectrometry, circular dichroism, and pharmacokinetic tests. 

Modifications of the standard battery may be necessary for some classes, e.g., antibiotics which are toxic to bacteria or e.g., for compounds like topoisomerase inhibitors which interfere with the mammalian cell replication system. A selection of additional assays is being proposed, further modifications may be acceptable via discussion in the ICH Maintenance Process. Alternative strategies may consider assays like the in vivo Comet assay (single cell gel electrophoresis measuring DNA strand breaks) or gene mutation tests with transgenic animals or in vivo DNA adduct studies. 

---