Transgenic Animals & Animal Models of Disease

Transgenic Animals & Animal Models of Disease

1. Definition, scope & why animal models matter

• An animal model of disease is a non-human species (most often a rodent) in which the process under investigation reproduces — as closely as possible — the disease profile seen in humans, so that hypotheses untestable in the target (human) species can be tested experimentally (Medhi Ch.1).
• The selection of an animal model is one of the most important steps in any experimental pharmacological study; the model chosen "must produce a similar disease profile as in the human" (Medhi Ch.1).
• Three guiding objectives for selecting a model species (Medhi Ch.1):
  • Use an animal phylogenetically closer to man; or
  • Use an animal in which the process under investigation is as close as possible to that in man; and
  • Ensure the anatomy, physiology and biochemistry are considered to be similar to the human counterpart.
• A general principle: "one species may be used as a model for another when, despite other differences between them, the two species strongly resemble each other in particular ways" (Medhi Ch.1).
• Transgenic technology is described by Medhi 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 has been altered (Medhi Ch.1).
• Overall rationale: genetically modified animals let pharmacologists (i) validate drug targets, (ii) dissect the molecular pathophysiology of disease, and (iii) test candidate compounds for on-target activity and mechanism-based toxicity before clinical trials (G&G 14e Ch.1; Vogel 4e; SK Gupta Ch.3).
• Position in the drug-development pipeline: model selection and genetic models sit within Stage II — preclinical studies (in vitro + in vivo animal experiments to define pharmacodynamics, pharmacokinetics, toxicity and the maximum recommended starting dose, MRSD), preceding Stage III clinical trials (Medhi Ch.1).

Part A — Transgenic animal technology (the genetic toolkit)