Journal of Molecular Medicine

, Volume 90, Issue 5, pp 597–608

Sequential targeting of CFTR by BAC vectors generates a novel pig model of cystic fibrosis

  • N. Klymiuk
  • L. Mundhenk
  • K. Kraehe
  • A. Wuensch
  • S. Plog
  • D. Emrich
  • M. C. Langenmayer
  • M. Stehr
  • A. Holzinger
  • C. Kröner
  • A. Richter
  • B. Kessler
  • M. Kurome
  • M. Eddicks
  • H. Nagashima
  • K. Heinritzi
  • A. D. Gruber
  • E. Wolf
Original Article

DOI: 10.1007/s00109-011-0839-y

Cite this article as:
Klymiuk, N., Mundhenk, L., Kraehe, K. et al. J Mol Med (2012) 90: 597. doi:10.1007/s00109-011-0839-y

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.

Keywords

Cystic fibrosisPig modelTranslational medicineBAC targetingNuclear transfer

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • N. Klymiuk
    • 1
  • L. Mundhenk
    • 2
  • K. Kraehe
    • 1
  • A. Wuensch
    • 1
  • S. Plog
    • 2
  • D. Emrich
    • 3
  • M. C. Langenmayer
    • 3
  • M. Stehr
    • 4
  • A. Holzinger
    • 5
  • C. Kröner
    • 1
  • A. Richter
    • 1
  • B. Kessler
    • 1
  • M. Kurome
    • 1
  • M. Eddicks
    • 6
  • H. Nagashima
    • 7
  • K. Heinritzi
    • 6
  • A. D. Gruber
    • 2
  • E. Wolf
    • 1
  1. 1.Institute of Molecular Animal Breeding and Biotechnology, Gene CenterLudwig-Maximilians-Universität MünchenMunichGermany
  2. 2.Department of Veterinary Pathology, Faculty of Veterinary MedicineFreie Universität BerlinBerlinGermany
  3. 3.Institute of Veterinary PathologyLudwig-Maximilians-Universität MünchenMunichGermany
  4. 4.Department of Pediatric Surgery, Dr. von Hauner Children’s HospitalLudwig-Maximilians-Universität MünchenMunichGermany
  5. 5.Division of Neonatology, Dr. von Hauner Children’s HospitalLudwig-Maximilians-Universität MünchenMunichGermany
  6. 6.Clinic for SwineLudwig-Maximilians-Universität MünchenOberschleißheimGermany
  7. 7.Laboratory of Developmental Engineering, Department of Life Science, School of AgricultureMeiji UniversityKawasakiJapan