Journal
ANIMAL MODELS AND EXPERIMENTAL MEDICINE
Volume 2, Issue 4, Pages 297-311Publisher
WILEY
DOI: 10.1002/ame2.12091
Keywords
animal models; CFTR channel activity; CFTR modulators; cystic fibrosis; primary cultures; rat
Funding
- Vaincre la Mucoviscidose
- Swiss CF Foundation (CFCH)
- Swiss National Foundation [310030_172909]
- Fondation Maladies Rares
- IRSR Pays de la Loire [RII-INSB-0014]
- IHU-CESTI [ANR-10-IBHU-005]
- France Life Imaging [ANR-11-INBS-0006]
- Infrastructures Biologie-Sante
- Swiss National Science Foundation (SNF) [310030_172909] Funding Source: Swiss National Science Foundation (SNF)
Ask authors/readers for more resources
BackgroundGenetically 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. MethodsWe 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. ResultsBoth 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. ConclusionsThe F508del rats reproduce the phenotypes observed in CFTR KO animals and represent a novel resource to advance the development of CF therapeutics.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available