Animal Model of disease
Principles of disease pathogenesis and the development of gene therapy approaches can often be addressed by studying animal models of human disease. Specific hypotheses and experimental therapies should generally be tested extensively in small animals prior to human experiments.The following questions are representative of those
that may be profitably addressed in animal experiments.
Can particular cell types serve as appropriate targets for gene therapy?
Can bone marrow expression of a gene product whose deficiency leads to a storage
disorder affecting the brain improve central nervous system function?
What fraction of cells of a tissue need to be altered genetically in order to
effect clinical improvement?
Are gene modified cells at a selective advantage or disadvantage in vivo?
Does the host develop an immune response to the gene transfer vehicles or to the
newly introduced gene product?
Animal models can provide an important link in the development of gene therapy
approaches, lying between gene discovery and characterization and clinical
experiments. Animal models also constitute a valuable resource for testing other
forms of therapy that are not based on gene transfer approaches.
Animal models for genetic diseases have arisen spontaneously in a variety of species (e.g., mouse, cat, dog). Using new methods to mutate genes in embryonic stem cells, mice with engineered alterations in any given gene can be produced. Numerous mouse strains with mutations in genes relevant to human diseases have already been created in this manner, and also by injection of human genes into fertilized mouse eggs. In some instances, mice with such mutations exhibit a phenotype similar to that seen in humans (examples: chronic granulomatous disease, hemophilia A, spinocerebellar ataxia1). In others, the effects of specific mutations in the mouse appear more severe than in humans (examples: ADA deficiency, Gaucher's disease).
Unfortunately, however, mouse models often do not faithfully mimic the relevant human conditions. For example, hypoxanthine phosphoribosyltransferase deficiency associated with LeschNyhan disease in humans is benign in mice due to the presence of an alternative metabolic pathway. Mice with mutations in the CFTR gene do not exhibit the pulmonary effects of cystic fibrosis seen in man, but rather suffer from severe gastrointestinal obstruction. Studying the differences between human diseases and animal model phenotypes may provide insights into disease pathogenesis that may, in turn, be exploited either by gene therapy or pharmacological approaches. Animal models for many cancers and for HIV infection have also been developed. In these instances, the relevance of animal models to human disease appears less certain than in typical singlegene disorders.
Despite potential phenotypic differences between human patients and animal models of disease, the study of animal models for the design of gene therapy approaches in a preclinical setting is important and should not be undervalued. As additional genes leading to human diseases are isolated, and gene targeting and transgenic technologies generate more mouse models of various human diseases, we should anticipate an increasingly productive use of such models to elucidate disease pathophysiology, possibly leading to gene therapy approaches.
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I'm sure the following article came from Dr. James M. Wilson, IHGT in the University of Pennsylvania, can tell you a lot on this topic:
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