RGD Reference Report - Characterization of two rat models of cystic fibrosis-KO and F508del CFTR-Generated by Crispr-Cas9. - Rat Genome Database

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Characterization of two rat models of cystic fibrosis-KO and F508del CFTR-Generated by Crispr-Cas9.

Authors: Dreano, Elise  Bacchetta, Marc  Simonin, Juliette  Galmiche, Louise  Usal, Claire  Slimani, Lotfi  Sadoine, Jérémy  Tesson, Laurent  Anegon, Ignacio  Concordet, Jean-Paul  Hatton, Aurélie  Vignaud, Lucile  Tondelier, Danielle  Sermet-Gaudelus, Isabelle  Chanson, Marc  Cottart, Charles-Henry 
Citation: Dreano E, etal., Animal Model Exp Med. 2019 Nov 25;2(4):297-311. doi: 10.1002/ame2.12091. eCollection 2019 Dec.
RGD ID: 126928119
Pubmed: PMID:31942562   (View Abstract at PubMed)
PMCID: PMC6930998   (View Article at PubMed Central)
DOI: DOI:10.1002/ame2.12091   (Journal Full-text)

Background: Genetically engineered animals are essential for gaining a proper understanding of the disease mechanisms of cystic fibrosis (CF). The rat is a relevant laboratory model for CF because of its zootechnical capacity, size, and airway characteristics, including the presence of submucosal glands.
Methods: We describe the generation of a CF rat model (F508del) homozygous for the p.Phe508del mutation in the transmembrane conductance regulator (Cftr) gene. This model was compared to new Cftr-/- rats (CFTR KO). Target organs in CF were examined by histological staining of tissue sections and tooth enamel was quantified by micro-computed tomography. The activity of CFTR was evaluated by nasal potential difference (NPD) and short-circuit current measurements. The effect of VX-809 and VX-770 was analyzed on nasal epithelial primary cell cultures from F508del rats.
Results: Both newborn F508del and Knock out (KO) animals developed intestinal obstruction that could be partly compensated by special diet combined with an osmotic laxative. The two rat models exhibited CF phenotypic anomalies such as vas deferens agenesis and tooth enamel defects. Histology of the intestine, pancreas, liver, and lungs was normal. Absence of CFTR function in KO rats was confirmed ex vivo by short-circuit current measurements on colon mucosae and in vivo by NPD, whereas residual CFTR activity was observed in F508del rats. Exposure of F508del CFTR nasal primary cultures to a combination of VX-809 and VX-770 improved CFTR-mediated Cl- transport.
Conclusions: The F508del rats reproduce the phenotypes observed in CFTR KO animals and represent a novel resource to advance the development of CF therapeutics.

Disease Annotations    

Gene-Chemical Interaction Annotations    
amiloride  (EXP,ISO)

Gene Ontology Annotations    

Biological Process

Objects Annotated

Genes (Rattus norvegicus)
Cftr  (CF transmembrane conductance regulator)
Cftrem1Ang  (cystic fibrosis transmembrane conductance regulator; CRISPR/Cas9 induced mutant 1, Ang)
Cftrem2Ang  (cystic fibrosis transmembrane conductance regulator; CRISPR/Cas9 induced mutant 2, Ang)

Genes (Mus musculus)
Cftr  (cystic fibrosis transmembrane conductance regulator)

Genes (Homo sapiens)
CFTR  (CF transmembrane conductance regulator)

SD-Cftrem1Ang  (NA)
SD-Cftrem2Ang  (NA)

Additional Information