Use of genetically modified rat models for translational medicine

genOway, Avenue Jean Jaur├Ęs, Immeuble Chateaubriand, Lyon, France.
Drug Discovery Today (Impact Factor: 6.69). 07/2008; 13(11-12):488-94. DOI: 10.1016/j.drudis.2008.03.021
Source: PubMed


Because of its relevance to human physiology, the rat may provide highly predictable models for the pharmaceutical industry. Until recently, the lack of efficient tools to manipulate the rat genome has drastically limited the use of this research model. Recent advances in gene expression and transgenic systems have provided new possibilities for the generation of informative rat models. This review presents a state-of-the-art transgenic technologies in the rat and their application to biomedical research. Novel technologies enabling the faithful expression of human genes in rats are focussed on specifically.

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    • "While mice have proven to be a useful model and techniques have been developed for routine disruption of their genes, in many circumstances rats are considered a superior laboratory animal for studying and modeling human disease. Rats are more similar to humans physiologically and are a better model for human cardiovascular disease, diabetes, and arthritis; for autoimmune, neurological, behavioral and addiction disorders; as well as for neural regeneration, transplantation, and wound and bone healing.3,4 In addition, rat models are excellent for testing the pharmacodynamics and toxicity of potential therapeutic compounds.5 "
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    ABSTRACT: The rational engineering of eukaryotic genomes would facilitate the study of heritable changes in gene expression and offer enormous potential across basic research, drug-discovery, bioproduction and therapeutic development. A significant advancement toward this objective was achieved with the advent of a novel technology that enables high-frequency and high-fidelity genome editing via the application of custom designed zinc finger nucleases (ZFNs). A ZFN is a chimeric protein that consists of the non-specific endonuclease domain of FokI fused to a DNA-binding domain composed of an engineered zinc-finger motif. Within these chimeric proteins, the DNA binding specificity of the zinc finger protein determines the site of nuclease action. Once the engineered ZFNs recognize and bind to their specified locus, it leads to the dimerization of the two nuclease domains on the ZFNs to evoke a double-strand break (DSB) in the targeted DNA. The cell then employs the natural DNA repair processes of either non-homologous end joining (NHEJ) or homology-directed repair (HDR) to repair the targeted break. Due to the imperfect fidelity of NHEJ, a proportion of DSBs within a ZFN-treated cellular population will be misrepaired, leading to cells in which variable heterogeneous genetic insertions or deletions have been made at the target site. Alternatively, the HDR repair pathway enables precise insertion of a transgene or other defined alterations into the targeted region. By this approach, a donor template containing the transgene flanked by sequences that are homologous to the regions either side of the cleavage site is co-delivered into the cell along with the ZFNs. By creating a specific DSB, these cellular repair mechanisms are harnessed to generate precisely targeted genomic edits resulting in both cell lines and animal models with targeted gene deletions, integrations, or modifications. This review will discuss the development, mechanism of action, and applications of ZFN technology to genome engineering and the creation of animal models.
    Annals of Neurosciences 01/2011; 18(1):25-28. DOI:10.5214/ans.0972.7531.1118109
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    • "2002 This transfer is not dependent on the size, localization or visualization of the nucleus Transgene insertion site may also modify the expression of genes at and around the site of integration Pfeifer. 2004 Single integrations of DNA are more often achieved High rates of mosaicisms van den Brandt et al. 2004 Lentiviviral vectors are able to transduce dividing and nondividing cells Dann et al. 2006 Dann 2007 Robl et al. 2007 Cozzi et al. 2008 Kanatsu-Shinohara et al. 2008 Cell Mol Neurobiol "
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    ABSTRACT: The rat is a model of choice in biomedical research for over a century. Currently, the rat presents the best "functionally" characterized mammalian model system. Despite this fact, the transgenic rats have lagged behind the transgenic mice as an experimental model of human neurodegenerative disorders. The number of transgenic rat models recapitulating key pathological hallmarks of Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, or human tauopathies is still limited. The reason is that the transgenic rats remain more difficult to produce than transgenic mice. The gene targeting technology is not yet established in rats due to the lack of truly totipotent embryonic stem cells and cloning technology. This extremely powerful technique has given the mouse a clear advantage over the rat in generation of new transgenic models. Despite these limitations, transgenic rats have greatly expanded the range of potential experimental approaches. The large size of rats permits intrathecal administration of drugs, stem cell transplantation, serial sampling of the cerebrospinal fluid, microsurgical techniques, in vivo nerve recordings, and neuroimaging procedures. Moreover, the rat is routinely employed to demonstrate therapeutic efficacy and to assess toxicity of novel therapeutic compounds in drug development. Here we suggest that the rat constitutes a slightly underestimated but perspective animal model well-suited for understanding the mechanisms and pathways underlying the human neurodegenerative disorders.
    Cellular and Molecular Neurobiology 04/2009; 29(6-7):859-69. DOI:10.1007/s10571-009-9367-5 · 2.51 Impact Factor
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    • "Compared to thousands of transgenic mice reported, the availability of transgenic rats is limited to about 100 transgenic lines characterized 1, 30-32. As transgenic technology advances in rats 1, 2, the number of transgenic rats is increasing at an accelerated speed 1, 33, 34. To express genes of interest in a conditional pattern in rats, we developed transgenic rats carrying and expressing tetracycline-controlled transactivator (tTA) under the control of a ubiquitous promoter. "
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    ABSTRACT: To develop transgenic lines for conditional expression of desired genes in rats, we generated several lines of the transgenic rats carrying the tetracycline-controlled transactivator (tTA) gene. Using a vigorous, ubiquitous promoter to drive the tTA transgene, we obtained widespread expression of tTA in various tissues. Expression of tTA was sufficient to strongly activate its reporter gene, but was below the toxicity threshold. We examined the dynamics of Doxycycline (Dox)-regulated gene expression in transgenic rats. In the two transmittable lines, tTA-mediated activation of the reporter gene was fully subject to regulation by Dox. Dox dose-dependently suppressed tTA-activated gene expression. The washout time for the effects of Dox was dose-dependent. We tested a complex regime of Dox administration to determine the optimal effectiveness and washout duration. Dox was administered at a high dose (500 microg/ml in drinking water) for two days to reach the effective concentration, and then was given at a low dose (20 microg/ml) to maintain effectiveness. This regimen of Dox administration can achieve a quick switch between ON and OFF statuses of tTA-activated gene expression. In addition, administration of Dox to pregnant rats fully suppressed postnatal tTA-activated gene expression in their offspring. Sufficient levels of Dox are present in mother's milk to produce maximal efficacy in nursing neonates. Administration of Dox to pregnant or nursing rats can provide a continual suppression of tTA-dependent gene expression during embryonic and postnatal development. The tTA transgenic rat allows for inducible and reversible gene expression in the rat; this important tool will be valuable in the development of genetic rat models of human diseases.
    International journal of biological sciences 02/2009; 5(2):171-81. · 4.51 Impact Factor
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