DOI: 10.1002/ame2.12091
Characterization of two rat models of cystic fibrosis—KO and F508del CFTR—Generated by Crispr-Cas9
Elise Dreano
Marc Bacchetta
Juliette Simonin
Louise Galmiche
Claire Usal
Lotfi Slimani
Jérémy Sadoine
Laurent Tesson
Ignacio Anegon
Jean-Paul Concordet
Aurélie Hatton
Lucile Vignaud
Danielle Tondelier
Isabelle Sermet-Gaudelus
Marc Chanson
Charles-Henry Cottart
1.INSERM 1151, INEM, Université de Paris, Paris, France2.Département de Pédiatrie, Gynécologie & Obstétrique et Département de Physiologie Cellulaire & Métabolisme, Université de Genève, Genève, Switzerland3.Département de Pathologie, APHP, CHU Necker-Enfants Malades, Paris, France4.Centre de Recherche en Transplantation & Immunologie, UMR 1064, INSERM, Université de Nantes, Nantes, France;Plateforme Trangénèse Rat & ImmunoPhénomique, INSERM 1064 & SFR Fran?ois Bonamy, CNRS UMS3556, Nantes, France5.Pathologie, Imagerie & Biothérapies Orofaciales, Montrouge, France;Plateforme Imageries du vivant, Faculté de chirurgie dentaire, Université de Paris, Paris, France6.Pathologie, Imagerie & Biothérapies Orofaciales, Montrouge, France7.INSERM U1154, CNRS UMR7196, MNHN, TACGENE, Paris, France8.INSERM 1151, INEM, Université de Paris, Paris, France;AP-HP, Centre Maladie Rare Mucoviscidose et Maladies du CFTR, Assistance Publique H?pitaux de Paris, H?pital Necker-Enfants Malades, Paris, France;Faculté de Médecine de Paris, Université de Paris, Paris, France9.INSERM 1151, INEM, Université de Paris, Paris, France;AP-HP, Centre Maladie Rare Mucoviscidose et Maladies du CFTR, Assistance Publique H?pitaux de Paris, H?pital Necker-Enfants Malades, Paris, France;Faculté de Pharmacie de Paris, Université de Paris, Paris, France
摘要：Background: Genetically engineered animals are essential for gaining a proper un-derstanding 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 charac-teristics, 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 poten-tial 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 ob-struction 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 cul-tures 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 ani-mals and represent a novel resource to advance the development of CF therapeutics.
机标关键词：tooth enamelcystic fibrosisnovel resourcecell culturesvas deferensrat model
论文发表日期：2019-01-01
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：15( 297-311 )
英文信息