Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Feb 27, 2018; 10(2): 277-286
Published online Feb 27, 2018. doi: 10.4254/wjh.v10.i2.277
Homologous recombination mediates stable Fah gene integration and phenotypic correction in tyrosinaemia mouse-model
Norman Junge, Qinggong Yuan, Thu Huong Vu, Simon Krooss, Christien Bednarski, Asha Balakrishnan, Toni Cathomen, Michael P Manns, Ulrich Baumann, Amar Deep Sharma, Michael Ott
Norman Junge, Thu Huong Vu, Ulrich Baumann, Department of Pediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover 30625, Germany
Qinggong Yuan, Asha Balakrishnan, Michael P Manns, Amar Deep Sharma, Michael Ott, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover 30625, Germany
Qinggong Yuan, Simon Krooss, Asha Balakrishnan, Michael Ott, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover 30625, Germany
Christien Bednarski, Toni Cathomen, Medical Center, University of Freiburg, Institute for Cell and Gene Therapy, Freiburg 79108, Germany
Amar Deep Sharma, Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover 30625, Germany
Author contributions: Junge N was involved in conception and design of the research, performed the majority of the experiments, analysed the data and wrote the manuscript; Yuan QG performed mouse surgery and immunostaining and revised the work critically for important intellectual content; Huong Vu T had substantial contributions to the experiments, animal care and analysis and interpretation of data for the work; Krooss S, Bednarski C, Balakrishnan A and Cathomen T helped with the experiments and design of the research and revised the work critically for important intellectual content; Manns MP and Baumann U revised the work critically for important intellectual content; Sharma AD and Ott M were initiator and supervisor of the work, the developed initial concept and design of the research and conducted important preliminary studies.
Institutional animal care and use committee statement: All experiments were approved and performed according to guidelines and ethical regulations from Hannover Medical School and local government.
Conflict-of-interest statement: There are no conflicts of interest for any of the authors regarding this work.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author (
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Michael Ott, MD, Full Professor, TWINCORE, Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str 7, Hannover 30625, Germany.
Telephone: +49-511-220027120 Fax: +49-511-220027178
Received: December 7, 2017
Peer-review started: December 8, 2017
First decision: December 18, 2017
Revised: February 1, 2018
Accepted: February 23, 2018
Article in press: February 23, 2018
Published online: February 27, 2018
Core Tip

Core tip: Recombinant adeno-associated virus (rAAV) has been explored for gene delivery in various murine models of hereditary liver disease, but in young children transgene expression from AAV-epigenomes diminishes over time. We thus explored, whether homologous recombination-mediated targeted gene addition of the fumarylacetoacetate hydrolase (Fah) gene would stably correct tyrosinaemia in rapidly proliferating livers of Fah-/- mice. Here, we report successful homologous recombination-mediated genome editing of a Fah gene expression cassette at the Rosa26 locus by rAAV8. We demonstrate that this approach corrects the phenotype and is long lasting in a proliferating state of the liver, as shown by serial transplantation.