New tools for genetically modified rodents development – SOURIRAT

The generation of genetically modified mice and rats is indispensable for the functional analysis of genes, the generation of disease models, the development of new drugs and for biothechnological applications. Until now, the best tool for genetic engineering of the mouse genome have been the embryonic stem (ES) cells but this technology is long (~1 year) and expensive (dozens of thousand Euros). The rat, despite its importance as a physiological model does not have robust ES cells technologies (1).
In the last 4 years, the spectrum of genetic engineering tools has enriched at a very rapid pace. This is in particular the case with the so called gene specific nucleases, such as méganucléases, ZFNs, TALENs and the very recently described CRISPR. These gene specific nucleases have radically changed the genetic engineering of many species through transgenesis, of cells and therapies such as gene therapy. Gene-specific nucleases were chosen as molecules of the year in 2011 by Nature Methods (2). The platform Transgenèse Rat Nantes (TRN) [national label IBiSA, (www.tgr.nantes.inserm.fr/)] at the INSERM 1064 was among the first one world-wide to apply them for the generation of rats with gene inactivated genes (3-5). It is also developing rat stem cells of ES and induced pluripotent (iPS) type.
The company genOway is one of the leading companies world-wide in the generation of genetically engineered mice and rats (www.genoway.com) . The company invests strongly in RD activities, as evidenced by the first publication of a rat cloned by nuclear transfer (6).
The platform TRN and genOway propose a research program centered on these new gene-specific nucleases, particularly CRISPRs, aiming to strongly reduce costs and timing of the development of genetically engineered mice and rats. These modifications will be with high scientific impact and by homologous recombination, such as punctual mutations, gene humanization, conditional and/or induced transgene expression, ablation or labeling of specific cellular lineages. Besides these objectives and as complementary approaches the LabCom will develop other technologies, such as rat iPS and protein degradation induced in vivo.
After the LabCom period and if success is obtained, the partnership will be consolidated through the creation of a branch of genOway in Nantes.
Economical valorization will be developed through patents co-developed between genOway and INSERM) as well as by the commercialization by genOway of these technologies and by the proposal of these services by TRN.
1. Aitman, T. J., et al. (2008) Progress and prospects in rat genetics: a community view. Nat Genet 40, 516-522
2. Editorial (2012) Method of the Year 2011. Nat Methods 9, 1
3. Geurts, A. M., Cost, G. J., Freyvert, Y., Zeitler, B., Miller, J. C., Choi, V. M., Jenkins, S. S., Wood, A., Cui, X., Meng, X., Vincent, A., Lam, S., Michalkiewicz, M., Schilling, R., Foeckler, J., Kalloway, S., Weiler, H., Menoret, S., Anegon, I., Davis, G. D., Zhang, L., Rebar, E. J., Gregory, P. D., Urnov, F. D., Jacob, H. J., and Buelow, R. (2009) Knockout rats via embryo microinjection of zinc-finger nucleases. Science 325, 433
4. Tesson, L., Usal, C., Menoret, S., Leung, E., Niles, B. J., Remy, S., Santiago, Y., Vincent, A. I., Meng, X., Zhang, L., Gregory, P. D., Anegon, I., and Cost, G. J. (2011) Knockout rats generated by embryo microinjection of TALENs. Nat Biotechnol 29, 695-696
5. Menoret, S., Fontaniere, S., Jantz, D., Tesson, L., Thinard, R., Remy, S., Usal, C., Ouisse, L. H., Fraichard, A., and Anegon, I. (2013) Generation of Rag1-knockout immunodeficient rats and mice using engineered meganucleases. Faseb J 27, 703-711
6. Zhou, Q., Renard, J. P., Le Friec, G., Brochard, V., Beaujean, N., Cherifi, Y., Fraichard, A., and Cozzi, J. (2003) Generation of fertile cloned rats by regulating oocyte activation. Science 302, 1179