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 c...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(F508 del) homozygous for the p.Phe508 del 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 F508 del rats.Results: Both newborn F508 del 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 F508 del rats. Exposure of F508 del CFTR nasal primary cultures to a combination of VX-809 and VX-770 improved CFTR-mediated Cl-transport.Conclusions: The F508 del rats reproduce the phenotypes observed in CFTR KO animals and represent a novel resource to advance the development of CF therapeutics.展开更多
基金TEFOR,Grant/Award Number:RIIINSB-0014France Life Imaging,Grant/Award Number:ANR-11-INBS-0006+6 种基金Swiss Cystic Fibrosis Foundation CFCHFondation Maladies RaresInfrastructures Biologie-SantéIHU-CESTI,Grant/Award Number:ANR-10-IBHU-005IRSR Pays de la LoireVaincre la MucoviscidoseSwiss National Foundation,Grant/Award Number:310030_172909
文摘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(F508 del) homozygous for the p.Phe508 del 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 F508 del rats.Results: Both newborn F508 del 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 F508 del rats. Exposure of F508 del CFTR nasal primary cultures to a combination of VX-809 and VX-770 improved CFTR-mediated Cl-transport.Conclusions: The F508 del rats reproduce the phenotypes observed in CFTR KO animals and represent a novel resource to advance the development of CF therapeutics.
