Animal models of lysosomal storage diseases: their development and clinical relevance

Excerpt

Progress in understanding how a particular genotype produces the phenotype of an inborn error of metabolism in human patients has been facilitated by the study of animals with mutations in the orthologous genes. These are not just animal 'models', but true orthologues of the human genetic disease, with defects involving the same evolutionarily conserved genes and the same molecular, biochemical and anatomical pathology as in human patients. Such animal orthologues are an important aid to the development of specific gene therapies for these disorders. The initial approach to finding suitable animals was to identify those with a naturally occurring disease. These animals were often domesticated species, because of the individual attention paid to such animals, particularly dogs and cats. In addition, naturally occurring mouse models have been found, and breeding lines established. Within the last several decades, advances in molecular biology and our understanding of murine reproductive physiology have combined to allow the production of knockout mouse models of human genetic disease expressed on various inbred backgrounds. Inbred strains of a small prolific species, such as the mouse, together with larger out-bred animals, discovered because of their disease phenotype, provide a powerful combination with which to elucidate the pathogenesis of human genetic disease and to investigate approaches to therapy. This has been true for inborn errors of metabolism and, in particular, the lysosomal storage diseases.