Knockout Rat Model Development

 

Rats are superior rodent models, making them ideal tools for testing the pharmacodynamics and toxicity of potential therapeutic compounds, and the reason they are widely used in medical research fields, including, but not limited to:
  • Cardiovascular disease
  • Psychiatric disorders
  • Neural regeneration
  • Diabetes
  • Transplantation
  • Autoimmune disorders
  • Cancer
  • Wound and bone healing

The Comeback of Rats

The first mammalian species to have been expressly used in the laboratory is the rat. However, when targeted gene manipulations became possible in the late 1980s, mice models became the tool of choice, because conventional techniques rely on embryonic stem (ES) cells, and ES cells from rats were simply not amenable to targeting.

Today, thanks to recent breakthroughs in genome editing technologies, including the CRISPR/Cas9 system, rat models are being reconsidered in the study and modeling of human diseases.

 

Remember Ralph?

Ralph - The world's first cloned ratAt genOway, in partnership with the National Institute of Agronomic INRA, we produced the world's first cloned rat, which we named Ralph [Zhou et al., Science, 2003].
Since then, we are heavily investing in research collaboration aiming at improving the creation of genetically modified rat models.

Important milestones in our rat history:

2016 Targeted sequence insertion in rats with CRISPR/Cas9 and TALE nucleases [Renaud et al., 2016]
2014-2016 Routine generation of Knockout and point mutation rat models using the CRISPR/Cas9 system
Numerous R&D projects for generating Knockin rat models
2015 Gene targeting in rats using Cas9 and TALEN engineered proteins [Ménoret et al., 2015]
2014 Gene targeting in rats using TALE nucleases [Remy et al., 2014]
2012 Immunodeficient rats engineered by meganucleases [Menoret et al., 2012]
2010 Two book chapters in Rat Genomics on practical guidelines for RNAi working in rats [Petit et al., 2010], and on somatic cell nuclear transfer in rats [Cozzi et al., 2010]
2006-2010 SME member and reference partner for rat ES cell line evaluation of the Sixth European Framework Program EURATools (European Rat Tools for Functional Genomics), exploring the genetic basis of rat disease characteristics and improving rat models for study of common human diseases
2009 Book chapter in Transgenesis Techniques on pronuclear DNA injection in rats [Cozzi et al., 2009]
2008 Review on “Use of genetically modified rat models for translational medicine” [Cozzi J et al. 2008]
2005-2008 Leading member of the ActivRat R&D project aiming at improving the efficacy of the cloning procedure in rats
2007 Provider of rat models for human diseases (ENU technology - chemically induced mutagenesis), in collaboration with the Hubrecht Institute, The Netherlands
2005 Review on “Transgenic modifications of the rat genome” [Tesson et al., 2005]
2003 Generation of the world’s first cloned rat, in partnership with the National Institute of Agronomic INRA [Zhou et al., Science, 2003]
2002 Initiation of genetic rat services, in collaboration with the French Institute of Health and Medical Research INSERM

 

Selection of genOway Clients' Publications on Rat Models

Pain

Micheli L, Di Cesare Mannelli L, Guerrini R, Trapella C, Zanardelli M, Ciccocioppo R, Rizzi A, Ghelardini C, Calò G.
Acute and subchronic antinociceptive effects of nociceptin/orphanin FQ receptor agonists infused by intrathecal route in rats.
Eur J Pharmacol. 2015

Galligan JJ, Patel BA, Schneider SP, Wang H, Zhao H, Novotny M, Bian X, Kabeer R, Fried D, Swain GM.
Visceral hypersensitivity in female but not in male serotonin transporter knockout rats.
Neurogastroenterol Motil. 2013

Thermoregulation

Lizarraga LE, Phan AV, Cholanians AB, Herndon JM, Lau SS, Monks TJ
Serotonin reuptake transporter deficiency modulates the acute thermoregulatory and locomotor activity response to 3,4-(±)-methylenedioxymethamphetamine, and attenuates depletions in serotonin levels in SERT-KO rats.
Toxicol Sci. 2014

Neuronal regeneration

Saheb-Al-Zamani M, Yan Y, Farber SJ, Hunter DA, Newton P, Wood MD, Stewart SA, Johnson PJ, Mackinnon SE.
Limited regeneration in long acellular nerve allografts is associated with increased Schwann cell senescence.
Exp Neurol. 2013

Sun HH, Saheb-Al-Zamani M, Yan Y, Hunter DA, Mackinnon SE, Johnson PJ.
Geldanamycin accelerated peripheral nerve regeneration in comparison to FK-506 in vivo.
Neuroscience. 2012

Moore AM, Borschel GH, Santosa KA, Flagg ER, Tong AY, Kasukurthi R, Newton P, Yan Y, Hunter DA, Johnson PJ, Mackinnon SE.
A transgenic rat expressing green fluorescent protein (GFP) in peripheral nerves provides a new hindlimb model for the study of nerve injury and regeneration.
J Neurosci Methods. 2012

Magill CK, Moore AM, Borschel GH, Mackinnon SE.
A new model for facial nerve research: the novel transgenic Thy1-GFP rat.
Arch Facial Plast Surg. 2010

Immunodeficiency

Ménoret S, Fontanière S, Jantz D, Tesson L, Thinard R, Rémy S, Usal C, Ouisse LH, Fraichard A, Anegon I.
Generation of Rag1-knockout immunodeficient rats and mice using engineered meganucleases.
FASEB J. 2013

Cardiac function

Pavlovic D, Hall AR, Kennington EJ, Aughton K, Boguslavskyii A, Fuller W, Despa S, Bers DM, Shattock MJ.
Nitric oxide regulates cardiac intracellular Na+ and Ca2+ by modulating Na/K ATPase via PKCε and phospholemman-dependent mechanism.
J Mol Cell Cardiol. 2013

Transplantation

Franquesa M, Herrero E, Torras J, Ripoll E, Flaquer M, Gomà M, Lloberas N, Anegon I, Cruzado JM, Grinyó JM, Herrero-Fresneda I.
Mesenchymal Stem Cell Therapy Prevents Interstitial Fibrosis and Tubular Atrophy in a Rat Kidney Allograft Model.
Stem Cells Dev. 2012

Parkinson disease

Lelan F, Boyer C, Thinard R, Rémy S, Usal C, Tesson L, Anegon I, Neveu I, Damier P, Naveilhan P, Lescaudron L.
Effects of Human Alpha-Synuclein A53T-A30P Mutations on SVZ and Local Olfactory Bulb Cell Proliferation in a Transgenic Rat Model of Parkinson Disease.
Parkinsons Dis. 2011

Hypertension

Patrick Davis R, Linder AE, Watts SW.
Lack of the serotonin transporter (SERT) reduces the ability of 5-hydroxytryptamine to lower blood pressure.
Naunyn Schmiedebergs Arch Pharmacol. 2011

Depression

Linder AE, Davis RP, Burnett R, Watts SW.
Comparison of the function of the serotonin transporter in the vasculature of male and female rats.
Clin Exp Pharmacol Physiol. 2011

Respiration

Ren W, Watts SW, Fanburg BL.
Serotonin transporter interacts with the PDGFβ receptor in PDGF-BB-induced signaling and mitogenesis in pulmonary artery smooth muscle cells.
Am J Physiol Lung Cell Mol Physiol. 2011

Anxiety

Rizzi A, Molinari S, Marti M, Marzola G, Calo' G.
Nociceptin/orphanin FQ receptor knockout rats: in vitro and in vivo studies.
Neuropharmacology. 2011

Drug abuse

Rutten K, De Vry J, Bruckmann W, Tzschentke TM.
Pharmacological blockade or genetic knockout of the NOP receptor potentiates the rewarding effect of morphine in rats.
Drug Alcohol Depend. 2011

Physiology

Linder AE, Beggs KM, Burnett RJ, Watts SW.
Body distribution of infused serotonin in rats.
Clin Exp Pharmacol Physiol. 2009

genOway's Rat Publications

Renaud JB, Boix C, Charpentier M, De Cian A, Cochennec J, Duvernois-Berthet E, Perrouault L, Tesson L, Edouard J, Thinard R, Cherifi Y, Menoret S, Fontanière S, de Crozé N, Fraichard A, Sohm F, Anegon I, Concordet JP, Giovannangeli C.
Improved Genome Editing Efficiency and Flexibility Using Modified Oligonucleotides with TALEN and CRISPR-Cas9 Nucleases.
Cell Rep. 2016

Ménoret S, De Cian A, Tesson L, Remy S, Usal C, Boulé JB, Boix C, Fontanière S, Crénéguy A, Nguyen TH, Brusselle L, Thinard R, Gauguier D, Concordet JP, Cherifi Y, Fraichard A, Giovannangeli C, Anegon I.
Homology-directed repair in rodent zygotes using Cas9 and TALEN engineered proteins.
Sci Rep. 2015

Remy S, Tesson L, Menoret S, Usal C, De Cian A, Thepenier V, Thinard R, Baron D, Charpentier M, Renaud JB, Buelow R, Cost GJ, Giovannangeli C, Fraichard A, Concordet JP, Anegon I.
Efficient gene targeting by homology-directed repair in rat zygotes using TALE nucleases.
Genome Res. 2014

Ménoret S, Fontanière S, Jantz D, Tesson L, Thinard R, Rémy S, Usal C, Ouisse LH, Fraichard A, Anegon I.
Generation of Rag1-knockout immunodeficient rats and mice using engineered meganucleases.
FASEB J. 2012

Book chapter: Cozzi J, Wang E, Jacquet C, Fraichard A, Cherifi Y, Zhou Q.
Procedures for somatic cell nuclear transfer in the rat.
Rat Genomics: Methods Mol Biol. 2010

Book chapter: Petit S, Thiam K.
Interference RNA for in vivo Knock-down of gene expression or genome-wide screening using shRNA.
Rat Genomics: Methods Mol Biol. 2010

Book chapter: Cozzi J, Anegon I, Braun V, Gross AC, Merrouche C, Cherifi Y.
Pronuclear DNA injection for the production of transgenic rats.
Transgenesis Techniques: Methods Mol Biol. 2009

Cozzi J, Fraichard A, Thiam K.
Use of genetically modified rat models for translational medicine.
Drug Discov Today 2008

Tesson L, Cozzi J, Menoret S, Remy S, Usal C, Fraichard A, Anegon I.
Transgenic modifications of the rat genome.
Transgenic Res. 2005

Zhou Q, Renard JP, Le Friec G, Brochard V, Beaujean N, Cherifi Y, Fraichard A, Cozzi J.
Generation of fertile cloned rats by regulating oocyte activation.
Science. 2003