Transgenic animals animal disease models

Animal models of disease play a critical role in the drug discovery process and are important in the lead candidate selection process as well. Categories of animal disease models include spontaneous disease, induced models (e.g., chemically, immunologically), xenograft models, infection models, and genetically modified models (e.g., transgenic knockouts (KOs) or knock-ins (KIs), humanized animals (e.g., expressing the human protein or receptor). The sub-... 

Selection of a relevant species and animal model to provide scientifically meaningful data requires an understanding of the phcirmacology and cross-species reactivity. Because these products tend to be species-specific, assessment of their toxicological potential may require the use of non-traditional animal models, such as transgenic mice and disease models. 

Conduct of studies with homologous proteins, clinically relevant animal disease models and transgenic animals... 

Most of the studies with these alternative models were conducted in discovery research. However, several respondents had conducted pivotal regulatory toxicity studies with homologous proteins and animal disease models, either to allow products such as MAbs and cytokines to be tested in man, or in support of regulatory toxicity studies by clarifying a finding. Only one respondent had conducted pivotal regulatory toxicity studies with transgenic animals in order to take a MAb into man. 

Transgenic animal models with spontaneous or induced receptor gene defects have been instrumental in elucidating the physiological roles of the LDL receptor gene family. In addition, a number of human diseases have been identified that are caused by sporadic or inherited forms of receptor deficiency (Table 1). 

Transgenic animals are produced by transferring cDNA into the pronucleus of a fertilized ovum. The resultant transgenic animal has the new gene (transgene) in all of its cells including its reproductive tissues. Transgenic animals are now widely used as experimental models in which to study human diseases. 

Offspring are tran enic New gene inserted is a transgene Design animal model for human disease this way... 

Genes are introduced, however, into the germlines of experimental animals such as mice to serve as models of human disease. These animals are called transgenic animals, and the introduced genes are termed transgenes. 

Identification of relevant drug targets, selection of drug receptor Q o Transgenic animals to probe complex in vivo systems, disease models... 

The Animal Species Selection section of the ICH document also refers to the use of homologous proteins and transgenic animals that express the human receptor. One example of a development program that relied on surrogates for safety assessment is that of infliximab [8], Many of the challenges of these models are acknowledged in this section. Animal models of disease are also discussed and can be used with strong scientific rationale. 

There has been explosive growth in the number of disease models in recent decades, especially in the field of the knockouts and transgenic rodents. A description of the most frequently used models alone would take a separate volume, and even that would be outdated within no time. Information on the selection of models and background data can easily be found on the Internet. The US National Center for Research Resources (NCRR) provides overviews and links [12], In addition the main providers of laboratory animals have very useful information on their Web sites. Readers looking for overviews on animal models per disease may find useful information in the Drug Discovery Today Disease Models review journal (http //www.drugdiscoverytoday.com). 

In recent years studies have been developed in spontaneous disease models, gene knock out models and transgenic animals. These models provide information on the pharmacological action, pharmaco-kinetics and tolerability of a biotech products. 

Brain and other tissue from sick experimental animals is as readily available as from healthy animals. That includes transgenic and other animals with model human diseases. But, it is vital to remember that mice are not men, nor are rats or other experimental animals. For instance, triple transgenic mice have been crafted that develop light microscopic lesions that mimic those of Alzheimer disease (AD). (Pietropaolo et al., 2009). However, direct molecular studies document that such triple gene mutations are not the cause of human AD (Tanzi et al., 1991). Treatments have been identified that benefit Alzheimer mice (Sung et al., 2004) but not human patients with this illness. (Petersen et al., 2005 Tabet et al., 2000)... 

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