Limitazioni dei modelli murini geneticamente modificati di malattie umane

[Bhogal N, Combes R. The relevance of genetically altered mouse models of human disease. Altern Lab Anim. 2006 Aug;34(4):429-54.]


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“Limitations and problems

The generation of a single GA mouse strain can require the use of very large numbers of animals, because: a) the mutagenesis methods are inefficient; b) there is poor germline transmission of gene mutations; and c) genetic modification can adversely affect fecundity and survival. These problems are so acute that, in many studies, a large proportion of the animals are incidental to the work, since they are merely used for breeding or are offspring that fail to carry the desired mutation or lack a novel and detectable phenotype. Also, even if the desired GA mice are created, they are not always good models of human disease, for several fundamental reasons. These include the fact that humans are about 3000 times larger than mice; they possess a much greater number of cells, some of which have to communicate over long distances; and the lifespans of mice and humans are vastly different. Moreover, there is a lower likelihood that errors within the mouse genome will eventually result in chronic diseases such as cancer, due to the greatly reduced number of cell divisions that occur in the body of this species over its lifetime, as compared with humans (see Mouse modelsof cancer, DNA repair disorders and their use in toxicity testing).

We have stated earlier that the mouse and human genomes have similar gene clusters and mice possess gene homologues to many human genes. However, despite this, and despite the fact that the average similarity between mouse and human genes is 85%, with similarity ranging from 70–95% for specific genes, a single nucleotide difference can dramatically alter the function of the protein expressed. Such subtle changes can have important phenotypic consequences for a species, affecting physical characteristics, as well as biochemistry, physiology and pharmacology, leading via variations in temporal and spatial protein expression to species-specific metabolism, immune responses, sensory perception and endocrine functions.

Therefore, assumptions about the functional equivalence of homologous genes in mice and humans can be erroneous.


 “Are GA mice relevant and useful?

GA mouse models of human disease often lack relevance in the case of complex multigenic disorders.

Indeed, some studies in GA mice have been less informative than the corresponding investigations with less-complex organisms and cell culture systems.

This is particularly true for mouse models developed by using forward genetics, where an undefined number of mutations may have contributed to an overall phenotype which resembles a human disorder, but which may share few, if any, of the underlying biochemical or genetic causes of the respective human disorders. The relevance of many transgenic mouse models can be questioned on the basis that, even if a species gene homologue has the same function and expression patterns and levels in humans and mice, all the remaining components of the biochemical pathway must be equally represented in the surrogate animal, if relevant mouse models of human diseases are to be created within a laboratory setting.


Over the past decade, there has been a dramatic shift toward the use of GA mice in research and testing, which has, in turn, prompted concerns about the welfare of the animals used. Issues such as reducing the number of animals wasted during the production of GM mice, and the effective welfare assessment of GA mice, remain causes for concern. The main question is whether the widespread use of GA mice can be scientifically justified. Only by addressing this question objectively, and without bias, can we hope to identify the scope for replacing GA mice in research and testing. It should be recognised that the generation of GA mice has often confused, rather than improved, our understanding of the genetic basis of human diseases.The large numbers of only partly-relevant models available for many diseases have complicated the meaningful extrapolation of the information they provide to human medicine. There is an urgent need to re-evaluate GA mice as models of human disease, to take into account the availability of alternative models based on studies on lower organisms, normal and diseased human cells, and the increasingly availability of other sources of human information of direct relevance.


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