Transgenic and genetically modified animals are being increasingly used in the study of diseases and for safety assessments of new compounds. They are a powerful tool for developing a more detailed understanding of the role specific genes play in biological pathways. The Federation of European Laboratory Animal Associations defines a transgenic animal as an animal in which there has been a deliberate modification of its genome.
The first transgenic mouse was created in 1974 by Rudolf Jaenisch, a biologist from MIT. He created this transgenic mouse through micro-injection of Simian virus 40 to explanted mouse blastocysts and early embryonic exposure to retrovirus. The technology to create transgenic animals broke new ground in the scientific community and enabled scientists to seek new ways of treating diseases and developing new drugs. The ability to introduce new genetic information into the germ line of complex organisms has completely changed and enhanced the study of all aspects of biologic processes.
The primary uses of transgenic mice models in toxicology have mainly been to screen for genotoxicity and carcinogenicity and to understand the mechanisms of toxicity. In preclinical safety testing, two-year mouse and rat bioassays are traditionally employed for predicting the potential risk of drugs/chemicals to induce cancer. These assays are time-consuming, use many animals (n=70/sex), and cost more than $1 million per study. Moreover, these traditional assays do not provide insight into the mechanisms of action nor explain key events leading to tumor formation.
The use of genetically modified mice for carcinogenicity evaluation began more than 20 years ago, when researchers found that different strains of genetically engineered mice demonstrated that cancer incidence is increased and tumor latency is decreased in mice whose germ line, the Ha-ras oncogene, has been inserted. Evaluation on carcinogenicity of newly developed pharmaceuticals using genetically modified animals has been performed since the adoption of ICH (International Conference on Harmonization) S1B guidelines on carcinogenicity testing of pharmaceuticals in 1997 and has increased greatly over the past 20 years, following this regulatory acceptance.
Improving Scientific Understanding
Conducting studies on transgenic animals provides an exclusive opportunity to improve scientific understanding of the mechanisms of carcinogenic compounds. Several transgenic mouse models (Tg.AC mice, ras transgenic mice, p53 knockout mice, Pim-1 mice, p27-deficient mice, and Xpa mice) have been studied for their usefulness as replacements for the lifetime bioassay in carcinogenicity testing. These mouse models could reliably predict the carcinogenic potential of compounds and significantly reduce the number of false positives. However, when applied as single assays, the transgenic models are unable to identify all known human carcinogens. Therefore, using a short-term transgenic mouse assay in combination with a two-year rat lifetime bioassay could eliminate the occurrence of false negatives.
Generally, TgrasH2 and p53+/- are mice models identified as acceptable for use as alternatives to the mouse long-term study together with a rat two-year bioassay; however, currently available data does not suggest that one model is more appropriate than the other for a particular class of compounds. This combined approach could further increase the overall accuracy of detecting carcinogens and non-carcinogens in comparison to using only the lifetime bioassays.
Incorporating a six-month transgenic mouse model into safety testing strategies for new drugs/chemicals makes valid scientific, ethical, and sound business sense, since these assays are shorter in duration, use fewer animals, and the cost is well below the traditional two-year mouse bioassay.
Ali Faqi, DVM, Ph.D., DABT, is senior director of developmental and reproductive toxicology and senior principal study director at MPI Research. Before joining MPI Research, Dr. Faqi was a senior scientist at Allergan Pharmaceuticals and a research toxicologist at IIT Research Institute.