Transplantation of gene-edited hepatocyte-like cells modestly improves survival of arginase-1 deficient mice

Sin, Y. Y., Ballantyne, L. L., Richmond, C. R. and Funk, C. D. (2018) Transplantation of gene-edited hepatocyte-like cells modestly improves survival of arginase-1 deficient mice. Molecular Therapy - Nucleic Acids, 10, pp. 122-130. (doi: 10.1016/j.omtn.2017.11.012)

Abstract

Progress in gene editing research has been accelerated by utilizing engineered nucleases in combination with induced pluripotent stem cell (iPSC) technology. Here, we report transcription activator-like effector nuclease (TALEN)-mediated reincorporation of Arg1 exons 7 and 8 in iPSCs derived from arginase-1 deficient mice possessing Arg1Δ alleles lacking these terminal exons. The edited cells could be induced to differentiate into hepatocyte-like cells (iHLCs) in vitro and were subsequently used for transplantation into our previously described (Sin et al., PLoS ONE 2013) tamoxifen-inducible Arg1-Cre arginase-1 deficient mouse model. While successful gene targeted repair was achieved in iPSCs containing Arg1Δ alleles, only minimal restoration of urea cycle function could be observed in the iHLC-transplanted mice compared to control mice and survival in this lethal model was extended by up to a week in some mice. The partially rescued phenotype may be due to inadequate regenerative capacity of arginase-1 expressing cells in the correct metabolic zones. Technical hurdles exist, and will need to be overcome for gene-edited iPSC to iHLC rescue of arginase-1 deficiency, a rare urea cycle disorder.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sin, Dr Angie
• Authors: Sin, Y. Y., Ballantyne, L. L., Richmond, C. R., and Funk, C. D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Molecular Therapy - Nucleic Acids
• Publisher: Elsevier (Cell Press)
• ISSN: 2162-2531
• ISSN (Online): 2162-2531
• Published Online: 01 December 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Molecular Therapy - Nucleic Acids 10: 122-130
• Publisher Policy: Reproduced under a Creative Commons License