Transgenic Animals & Animal Models of Disease

Introduction — why animal models matter

• Animal model of disease — a non-human species (most often a rodent) in which the process under investigation reproduces — as closely as possible — the human disease profile, letting hypotheses untestable in humans be tested experimentally. Model selection is one of the most important steps in any experimental-pharmacology study.
• Selection objectives — choose a species (1) phylogenetically closer to man, or (2) in which the process under study is as close as possible to that in man, with (3) anatomy, physiology & biochemistry considered similar to the human counterpart — "one species models another when, despite differences, the two strongly resemble each other in the feature studied."
• Transgenic technology — described as "one of the most powerful new genetic techniques" — the ability to produce transgenic animals (e.g. mice) in which the gene for a receptor or its endogenous ligand is altered, so function can be assigned by gain/loss of that gene.
• Why pharmacologists use them — genetically modified animals let us validate drug targets, dissect the molecular pathophysiology of disease, and test candidates for on-target activity & mechanism-based toxicity before clinical trials.
• Pipeline position — model selection and genetic models sit within Stage II — preclinical studies (in-vitro + in-vivo work defining PD, PK, toxicity and the maximum recommended starting dose, MRSD), preceding Stage III clinical trials.