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CRISPR-Cas9 is a rapid and cost effective technology to generate mutant models.

We offer the generation of knock-out models though direct injection into fertilized mouse oocytes of CRISPR sgRNA and Cas9 mRNA. This approach allows to obtain models in shorter timelines and with reduced costs compared to gene targeting by homologous recombination in ES cells.

Birling MC, Herault Y, Pavlovic G. Modeling human disease in rodents by CRISPR/Cas9 genome editingMamm Genome. 2017 Jul 4. View on Pubmed

Our offer involves:

  • Design of an optimized strategy including prediction of off-target sites
  • Preparation of sgRNA and Cas9 mRNA
  • Injection of sgRNA and Cas9 mRNA into zygotes, to generate F0 mutated animals
  • Genotyping of F0 animals and delivery of F0 candidate 
  • Optional steps (for mouse models):
    • Off-target analysis in F0 founder mice (optional)
    • Germline breeding of F0 founder mouse to achieve germ line transmission (optional)
    • Off-target analysis in germline transmitted F1 mouse (optional)

Awareness -CRISPR/Cas9 rodent genome editing- July 2017 (281.8 KB)

Technological jump: CRISPR Mediated REarrangement (CRISMERE) strategy

The Institut Clinique de la Souris (ICS) is a founding member of PHENOMIN, the national infrastructure for the generation and analysis of murine models. By adapting CRISPR / Cas9 technology, researchers of PHENOMIN and the IGBMC have been able to quickly and efficiently generate mouse models of diseases related to variations in the number of copies of certain regions of the genome. 

These results are published on March 2017 in Scientific reports

The CRISPR / Cas9 "revolution" 

Discovered in 2012, the technique known as "CRISPR / Cas9" allows to target DNA very precisely through a guide RNA. The latter is associated with an enzyme, Cas9, which makes it possible to cut, replace, inactivate or modify the targeted gene. More precise, faster and cheaper than all the techniques used to date, this method is now used in many laboratories to modify cells in vitro. Numerous studies have shown that its application in vivo is possible but the effectiveness of the methods remains limited in these cases. 

Easily create mouse and rat models 

To date, to create murine models, researchers use methods combining the Cre-Lox recombination system and the use of embryonic stem cells, but these processes are long and tedious, and it takes about 3-4 years to create a new mouse model. Here, scientists have adapted the CRISPR / Cas9 technique for the creation of mutant animals. They have doubled the RNA-guides, using two very similar guides to increase the efficiency of the break and have thus managed to modify important regions of the DNA (up to 24.4 Mb). Deletion, duplication, inversion, many configurations have been tested and validated by the generation of mouse lines carrying these mutations, and their transmission to the lineage. "The size of the targeted DNA section is not really a limiting factor, it's more the question of viability due to the removing certain genes that limits us" explains Marie-Christine Birling. Conclusion: it is now simple and fast (6-7 months) to create new disease models, good news for translational research. 

Mice and rat models of trisomy 21 

With this new method developed at the ICS, Yann Hérault and his team at IGBMC have created new mouse models of trisomy 21, a disease due to the presence of an additional copy of the chromosome 21. This was not possible with the previous techniques, but the researchers also succeeded in performing the same manipulations in the rat, thus creating an interesting model for evaluating behavior, knowledge, memory and social interactions. According to them this technique is adaptable to any species and its use could be made on human cells. 

This study has been financed by the ANR, the Fondation Jérôme Lejeune and the Fondation Bettencourt-Schueller.

New opportunities for researchers in their choice of the most suitable animal model.

To complete our mouse services and resources, ICS generates genetically engineered rat models through CRISPR/Cas9 genome editing.

The rat model sharing many physiological similarities with humans, it has long been a model favored by physiologists, pharmacologists and neuroscientists.

Their larger size allows to perform several experiments, surgical procedures and to monitor physiological parameters that are difficult or impossible in mice. Rat is a key model for cardiovascular disease studies: atherosclerosis, hypertension, stroke models, not only because of its size, but also because of its physiology. By their ability to learn and accomplish sophisticated behavioral tasks, rats are relevant model for nervous system diseases.

Now, CRISPR/Cas9 genome editing opens a new area in rat genetics.

you could request YOUR customized rat model for your OWN biomedical researches to PHENOMIN.

1-Jacob, H.J. & Kwitek, A.E. (2002) Multifactorial genetics: Rat genics: attaching physiology and pharmacology to the genome, Nat. Rev. Gen., 3(1), 33-42.

2-Cozzi J. et al., (2008) Use of genetically modified rat models for translational medicine, Drug Discovery Today, 13(11/12), 488-94.

3- Aitman TJ et al., (2008) Nat Genet. Progress and prospects in rat genetics: a community view. 2008 May; 40(5):516-22.

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