Transgenics spontaneous disease

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-... 

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. 

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). 

In the case of spontaneous autoimmune diseases mice are the most frequently used animal model. With the advent of transgenic and genetically modified (knockout, KO) mice, the number of genetically predisposed autoimmune models has substantially increased. Other species that have been useful include rats, monkeys, cats, dogs, rabbits, and chickens for some specific forms of autoimmune diseases [4, 5]. 

Cardiovascular disease models demonstrate aspects/features of humanized disease models. For hyperlipidemia-based atherosclerosis, there is a lack of a spontaneous in vivo mouse model because mice are resistant to (diet-induced) hyperlipidemia. Therefore a number of transgenic mice have been developed to better understand the pathogenesis in humans and obtain mouse models predictive of the human disease. Overexpression of ApoB, ApoE-variants, and knockout of ApoE, the LDL receptor or LPL (lipopro-... 

Even more interesting, transgenic mice expressing RL-mPrP spontaneously developed a full prion disease which was transmissible to transgenic mice overexpressing wild-type mouse PrP [55], As deer do not spontaneously develop CWD... 

The caveat with all of the current transgenic mouse models of familial TSE is that none precisely replicate the human disease. Almost all of them are dependent on transgenic mouse studies that involve both overexpression and random insertion of the transgene. In fact, when a single copy of a PrP mutant associated with GSS (proline to leucine at 102) is specifically substituted into the PrP gene locus, no spontaneous neurodegenerative disease is observed (Manson et al, 1999). Rather, an increased resistance to infection with scrapie is found (Manson et al,... 

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