Overview

Animal models - used both in vivo and in vitro - are indispensable yet imperfect tools that are infrequently predictive of response in humans. Animal models, almost exclusively in rats and mice, can provide only proof-of-concept. In fact, the US Food and Drug Administration (FDA) does not require that efficacy studies be carried out in animal models -only that drug developers provide a reasonable biological rationale for why they think a particular therapy might be effective. On the other hand, testing - in normal animals - is generally required to provide risk assessment data; beyond this, sponsors use animal models to identify therapeutic targets, and to convince themselves of a drugs potential efficacy before proceeding with its development. Ultimately, however, a potential therapeutic must be studied in humans, since beyond problems in predicting efficacy, many side effects (e.g., certain infections, nausea, and headache) cannot be detected in animal studies.

A flaw with many animal models is that they focus on replication of symptoms rather than pathogenic mechanisms. The fact that the fundamental differences between chronic and acute response in autoimmune disease are not understood also limits the development of appropriate animal models. In addition, there is often a mismatch between the observed pathology of the human and animal diseases - perhaps because the former tend to be from late stage, post-mortem analysis, while the animal data are often from the earliest stages of disease; indeed, because of the short life span of many animals, they may never develop the pathology seen in late-stage humans.

Drosophila melanogaster and other invertebrates have proven to be excellent model systems for many neuro-degenerative diseases that faithfully replicate key neuropathological features of the human disorders. Invertebrates have many advantages, particularly the possibility for sophisticated and rapid genetic analysis, the short life span, and modest cost. However, there are, as yet, no invertebrate models for autoimmune disease - although there are ongoing efforts to develop one for ALS. This is, in large part, due to the fact that Drosophila lacks an adaptive immune response, although it appears to have an innate immune response (humans have both).

Rodents are the most commonly utilized animal model in preclinical research. However, only a small fraction of the many treatments that proved effective in rodents with experimental autoimmune disease have reached the clinic. The reasons for these failures are numerous and diverse. The diseases are often chronic while the animal models are acute. Both rats and mice have the disadvantage of small brain and body size, which presents problems for imaging studies and longitudinal blood sampling; rabbits are sometimes substituted for just this reason. In addition, their relatively short life span, while offering obvious advantages, does not provide a good model for chronic therapies. Further, the diversity characteristic of all autoimmune diseases and syndromes may be lacking in rodent models utilizing inbred strains. Lastly, there are many immunological differences between rodents and humans, and laboratory rodents are generally pathogen-free, while patients have a long history of infections. With all that said, however, the advantages of rodents are real: genetically susceptible strains, transgenic animals (knockouts, knock-ins), numerous reagents developed for use in rodents, and cells and tissues that can be easily established in vitro.

Nonhuman primates have many advantages over rodents as models of human disease (cost is obviously not one of them). Foremost is their close immunological and genetic proximity to humans and their outbred nature. In addition,

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