Animal models human disease

Animal model Human disease equivalent Vitamin Drmediated effects, observations, proposed mechanisms References... 

Enzyme Animal model Human disease Reference... 

Target discovery, to identify genes or pathways with altered expression in diseased human tissues or in animal model of disease... 

Dunne C., Murphy L., Flynn S., O Mahony L., O Halloran S., Feeney M., Morrissey D., Thornton G., Fitzgerald G., Daly C., Kiely B., Quigley E.M.M., O Sullivan G.C., Shanahan F. and Collins J.K. et al., (1999). Probiotics, from myth to reality. Demonstration of functionality in animal models of disease and in human clinical trials . Antoine Van Leeuwenhoek, 76, 279-92. 

Animal models of disease, whether naturally occurring or artificially induced, provide valuable insights into human disease and allow rigidly controlled studies that are not possible in humans. Probably the most intensively studied model of an immune complex disease is the spontaneous lupuslike disease that occurs in certain inbred strains of mice, especially the (NZB x NZW) F, hybrid. Its study has provided insights with respect to genetic predisposition (H25), the role of endogenous retroviruses (D8), the influence of sex hormones (R9), the identification of T suppressor cell abnormalities (T3), and the propensity to form certain autoantibodies, especially to double-stranded DNA (S36) and to the RNA-protein complex, Sm (E2). Though animal studies are not the subject of this review, we emphasize that the entire concept and framework by which we view immune complex disease in humans are based on initial observations in animals. 

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-... 

The principle of estimating a therapeutic index prior to clinical trials typically involves determining the no observable adverse effect level (NOAEL) and comparing that to the projected human dose. In providing the estimate, the efficacious dose is typically obtained from in vitro data with human cells or tissues and in vivo preclinical pharmacology studies that involve animal disease models. Not infrequently the species used to estimate the toxic level is different from the species used to estimate an efficacious level. Thus the therapeutic index is not a true ratio as the units (species and/or conditions) are often different. On the other hand, if one were to obtain information relating to toxicity as well as efficacy from studies employing animal models of disease, a direct estimate of therapeutic index could be made provided that appropriate models had been characterized or validated in the relevant species. 

The decision on the use animal models of disease for assessing safety is based on a consideration of a number of factors, not the least of which is whether an animal model of disease is available for the intended disease. There are also ethical and welfare considerations as in any proposal to use animals in scientific work. Animal models of human disease may not mimic all aspects of disease or be more sensitive. However, as long as there is a good understanding of the human disease as well as acknowledgment of specific limitations of the model, studies should allow for better predictions of risk in the intended disease populations (see Table 3.4). 

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. 

These animal models of disease should be considered early on as potentially providing some of the data necessary for initiation of human studies. Besides utility as proof of concept, they can add to understanding dose response as well as help evaluate some safety endpoints. New products resulting from improved manufacturing can be compared with previously produced material using pharmacokinetic parameters. 

In many cases, only one relevant animal model of disease may be available to assess activity and/or safety in other cases, more than one model may be available and sufficiently characterized to allow for meaningful extrapolation. Two species, including larger animal species, can be used to assist extrapolation of dose to humans and/or to test the safety of cell-based product with the intended clinical delivery device. In the latter case, it is important to assess not only biocompatibility of the cells with the delivery device but the delivery reproducibility, namely the quantitative recovery of cells after injection based on the formulation and concentration to be used. 

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)... 

These data are all hard to obtain from human studies. The industry relies on animal models of diseases to validate their processes. How does or how should the industry approach multigenic diseases in animal models ... 

The quality of the biological data is paramount in the decision as to whether a given chemical is closer to, or further away from, the desired properties. This high level diagnosis is made from data derived from numerous sources. The confidence level is very much determined by the extent to which the chemistry and mechanism of action of the drug has been previously described. Since a disease model is only proven when it has been shown to predict a chemical activity in the human, it is only validated retrospectively. A novel therapy will require untested animal models of disease and so the confidence in the data derived from the model is substantially reduced. Similarly, new chemical entities having unknown metabolites are much more problematic in the prediction of adverse side effects. Therefore a chemist is conservative and more likely to work with classes of compounds previously shown to be safe. 

Levy and others (35,36) have developed an extensive literature which demonstrates in animal models of disease that the pharmacodynamics of a number of drugs are altered, even after controlling for pharmacokinetic changes. Studies with drugs administered as racemic mixtures in humans with renal dysfunction, hepatic dysfunction, and other disease states that address the issue of stereoselective pharmacodynamics are lacking. However, the cited animal studies suggest that such a line of investigation would be fruitful. 

Any of the above examples that can be assessed in both humans and animal models of disease. 

Mice and other animal models of disease are often poor mimics of the human condition. However, the expression of human genes in these animals can initiate development of the disease. In mice, the distribution of cholesterol between low-density lipoproteins (LDL) and high-density lipoproteins (HDL) is quite distinct from that in humans. However, if the human enzyme, cholesterol ester transfer protein (CETP) is expressed in mice, the ratio of LDL HDL becomes more human in profile. Inhibition of CETP is a target for antiatherosclerotic drags and there now exists an animal model in which to test them. 

It has become accepted that the main pharmaceutical areas where metabonomics is impacting include validation of animal models of disease, including genetically modified animals preclinical evaluation of drug safety studies allowing ranking of candidate compounds assessment of safety in humans in clinical trials after product launch, quantitation, or ranking of the beneficial effects of pharmaceuticals. 

The penultimate step in drug development is the testing of the drug candidate in animal models of disease, where all the complex interactions that underlie pathophysiological mechanisms take place. It is important that animal models not only manifest the relevant disease phenotype observed in humans, but that the underlying innate and adaptive immune responses are similar to the human disease. In the case of leishmaniasis, there are reasonably good animal models for some, but not all of the cutaneous forms. The animal models for visceral leishmaniasis are less satisfaaory. Nonetheless, the animal models for leishmaniasis are considerably better than those for other parasitic diseases. 

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