title: Sequential targeting of CFTR by BAC vectors generates a novel pig model of cystic fibrosis.
abstract: Cystic fibrosis (CF) is the most common lethal inherited disease in Caucasians and is caused by mutations in the CFTR gene. The disease is incurable and medical treatment is limited to the amelioration of symptoms or secondary complications. A comprehensive understanding of the disease mechanisms and the development of novel treatment options require appropriate animal models. Existing CF mouse models fail to reflect important aspects of human CF. We thus generated a CF pig model by inactivating the CFTR gene in primary porcine cells by sequential targeting using modified bacterial artificial chromosome vectors. These cells were then used to generate homozygous CFTR mutant piglets by somatic cell nuclear transfer. The homozygous CFTR mutants lack CFTR protein expression and display severe malformations in the intestine, respiratory tract, pancreas, liver, gallbladder, and male reproductive tract. These phenotypic abnormalities closely resemble both the human CF pathology as well as alterations observed in a recently published CF pig model which was generated by a different gene targeting strategy. Our new CF pig model underlines the value of the CFTR-deficient pig for gaining new insight into the disease mechanisms of CF and for the development and evaluation of new therapeutic strategies. This model will furthermore increase the availability of CF pigs to the scientific community.
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377 Munich, Germany. n.klymiuk@gen.vetmed.uni-muenchen.de
authors.forename: N
authors.initials: N
authors.lastname: Klymiuk
authors.forename: L
authors.initials: L
authors.lastname: Mundhenk
authors.forename: K
authors.initials: K
authors.lastname: Kraehe
authors.forename: A
authors.initials: A
authors.lastname: Wuensch
authors.forename: S
authors.initials: S
authors.lastname: Plog
authors.forename: D
authors.initials: D
authors.lastname: Emrich
authors.forename: M C
authors.initials: MC
authors.lastname: Langenmayer
authors.forename: M
authors.initials: M
authors.lastname: Stehr
authors.forename: A
authors.initials: A
authors.lastname: Holzinger
authors.forename: C
authors.initials: C
authors.lastname: Kröner
authors.forename: A
authors.initials: A
authors.lastname: Richter
authors.forename: B
authors.initials: B
authors.lastname: Kessler
authors.forename: M
authors.initials: M
authors.lastname: Kurome
authors.forename: M
authors.initials: M
authors.lastname: Eddicks
authors.forename: H
authors.initials: H
authors.lastname: Nagashima
authors.forename: K
authors.initials: K
authors.lastname: Heinritzi
authors.forename: A D
authors.initials: AD
authors.lastname: Gruber
authors.forename: E
authors.initials: E
authors.lastname: Wolf
mesh_terms: D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics*; D003550:Cystic Fibrosis / Q000235:genetics* / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005333:Fetus / Q000378:metabolism; D055786:Gene Knockout Techniques; D018390:Gene Targeting; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009928:Organ Specificity; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034421:Sus scrofa
chemical_list: D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator