Genetically Engineered Animals in Drug Discovery and Development: A Maturing Resource for Toxicologic Research

Abstract

Genetically engineered mice that either over-express a foreign gene (transgenic) or in which the activity of a specific gene has been removed ("knock-out") or replaced ("knock-in") will be used increasingly to investigate molecular mechanisms of disease, to evaluate innovative therapeutic targets, and to screen novel agents for efficacy and/or toxicity. Recent innovations of relevance to toxicologic researchers include the construction of genetically engineered mice with (1) multiple engineered genes, (2) mutations that can be induced at specific sites and times throughout life, and (3) the substitution of human genes for their mouse counterparts ("humanized" mice) to allow in vivo investigation of xenobiotic toxicity. Contemporary applications of genetically engineered mice in toxicology include basic mechanistic research exploiting newly engineered mouse lines as well as applied screening for genotoxicity and carcinogenicity using commercially available animals. Many caveats must be considered when interpreting genetically engineered mice-derived toxicity data, the chief of which will be the extent to which the model's phenotype has been fully characterized, the type and incidence of background lesions for the given mouse strain and engineered gene, and the possibility of misinterpreting the presence or absence of a phenotype due to compensatory physiologic processes that mask the outcome produced by the engineering event. Toxicity data acquired using genetically engineered mice currently supplements and in time likely will supplant those gathered using the present "gold standard" bioassays, as genetically engineered mice typically develop more lesions after a shorter latency period than do age- and strain-matched, wild-type mice.

Recent Advances in SPECT Imaging

“…Even more importantly, transgentic and knockout mice are now widely used in medical research to investigate the molecular mechanisms of disease (42)(43)(44). Because of their ability to detect very low (picomolar) concentrations of tracer materials, both PET and SPECT are very attractive modalities for molecular imaging in these animal models.…”

Internet Resources for Phenotyping Engineered Rodents

“…The truth of this assertion has been proven by the demonstration that pharmacological effects in humans of the 100 top-selling drugs correlate well with the anticipated outcome observed in GEM lacking the molecular targets for these agents (Zambrowicz and Sands 2003). Thus, the collective experience in this field indicates that GEM and GER add great value both to basic research programs designed to discover fundamental principles of mammalian physiology and to applied research efforts to define and correct molecular aberrations responsible for many human diseases (Bolon 2004).…”

Predictive Toxicology Approaches for Small Molecule Oncology Drugs

“…More recently, KO mice have been used to address questions concerning toxicity and the potential adverse consequences of target inhibition. Although KO mice can be used to explore the role of a specific target or pathway in mechanisms of toxicity, the practice of equating a phenotype of a genetically ablated animal with a potential adverse drug effect carries with it many important caveats (Bolon 2004;Ryffe 1997). Moreover, many oncology targets involve pathways that are essential for normal embryofetal development, which significantly limits the utility of this approach.…”