Humanized F508del mouse model: New preclinical model for cystic fibrosis?

Mottais, Angélique [UCL] Achouri, Younes [UCL] Beka, Mathilde [UCL] Marbaix, Etienne [UCL] Vande Velde, Greetje [KULeuven] Vanoirbeek, Jeroen [KULeuven] Gohy, Sophie [UCL] Leal, Teresinha [UCL] et al.[show all]

Animal models have been widely used to study pathophysiology of human diseases and efficacy of new therapies. In the context of cystic fibrosis (CF), several animal models have been developed. However, mouse model shows little or no severe respiratory phenotype typically associated with high morbidity and mortality of the human disease. Based on the observation that the F508del mutation of CFTR leads to a more severe CF phenotype for the human CFTR (hCFTR) than for the murine CFTR (mCFTR), this project aims at developing a CF mouse model expressing the hCFTR gene with F508del mutation. To this aim, two murine lines were generated and crossed: 1) a line deleted for the mCftr (generated by CRISPR/Cas9) and 2) a line over-expressing the hCFTR F508del (generated by transgenesis). The obtained mice were genotyped and characterized. For this purpose, the overall phenotype (viability, body weight curve and height), the expression of the hCFTR and mCftr genes and proteins, the chloride channel function (evaluated by nasal potential difference), the lung phenotype (inflammatory cytokines and cell count in the bronchoalveolar lavage, bronchopulmonary anatomopathological study, in vivo high-resolution micro-computed tomography and lung function exploration) were recorded. Our preliminary data including reduced growth, dental enamel defect and reduced chloride transport across the airway epithelium suggest that hCFTR-F508del mice present a typical CF phenotype similar to that reported in pre-established mouse models. Moreover, it will be necessary to refine the phenotypic characterization by assessing inflammatory responses following induction by well-established bacterial components and by the clinical response to modulators. Our new model will hopefully allow a better understanding of the genotype/phenotype differences between the hCFTR and the mCFTR and become a relevant preclinical model for the evaluation of new therapeutic strategies.