Reprogramming metabolic pathways in vivo with CRISPR/Cas9 genome editing to treat hereditary tyrosinaemia

Francis P. Pankowicz; Mercedes Barzi; Xavier Legras; Leroy Hubert; Tian Mi; Julie A. Tomolonis; Milan Ravishankar; Qin Sun; Diane Yang; Malgorzata Borowiak; Pavel Sumazin; Sarah H. Elsea; Beatrice Bissig-Choisat; Karl-Dimiter Bissig

doi:10.1038/ncomms12642

journal article Open Access Aug 30, 2016

Reprogramming metabolic pathways in vivo with CRISPR/Cas9 genome editing to treat hereditary tyrosinaemia

Francis P. Pankowicz Mercedes Barzi Xavier Legras Leroy Hubert Tian Mi

Julie A. Tomolonis

Milan Ravishankar Qin Sun

Diane Yang Malgorzata Borowiak Pavel Sumazin

Sarah H. Elsea Beatrice Bissig-Choisat Karl-Dimiter Bissig

Nature Communications Vol. 7 No. 1 · Springer Science and Business Media LLC

View at Publisher Save 10.1038/ncomms12642

Abstract

AbstractMany metabolic liver disorders are refractory to drug therapy and require orthotopic liver transplantation. Here we demonstrate a new strategy, which we call metabolic pathway reprogramming, to treat hereditary tyrosinaemia type I in mice; rather than edit the disease-causing gene, we delete a gene in a disease-associated pathway to render the phenotype benign. Using CRISPR/Cas9 in vivo, we convert hepatocytes from tyrosinaemia type I into the benign tyrosinaemia type III by deleting Hpd (hydroxyphenylpyruvate dioxigenase). Edited hepatocytes (Fah−/−/Hpd−/−) display a growth advantage over non-edited hepatocytes (Fah−/−/Hpd+/+) and, in some mice, almost completely replace them within 8 weeks. Hpd excision successfully reroutes tyrosine catabolism, leaving treated mice healthy and asymptomatic. Metabolic pathway reprogramming sidesteps potential difficulties associated with editing a critical disease-causing gene and can be explored as an option for treating other diseases.

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References

Details

Published: Aug 30, 2016
Vol/Issue: 7(1)
License: View

Authors

Department of Pediatrics, Division of Medical Genetics, Alice and Y.T. Chen Center for Genetics and Genomics, Duke University School of Medicine, Durham, North Carolina, USA

Department of Medicine Baylor College of Medicine Houston Texas

Beatrice Bissig-Choisat

K

Karl-Dimiter Bissig

Department of Pediatrics, Division of Medical Genetics, Alice and Y.T. Chen Center for Genetics and Genomics, Duke University School of Medicine, Durham, North Carolina, USA; Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina, USA; Department of Biomedical Engineering (BME) at the Duke University Pratt School of Engineering, Durham, North Carolina, USA; Duke Cancer Center, Duke University Medical Center, Durham, North Carolina, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA

Cite This Article

Francis P. Pankowicz, Mercedes Barzi, Xavier Legras, et al. (2016). Reprogramming metabolic pathways in vivo with CRISPR/Cas9 genome editing to treat hereditary tyrosinaemia. Nature Communications, 7(1). https://doi.org/10.1038/ncomms12642

Reprogramming metabolic pathways in vivo with CRISPR/Cas9 genome editing to treat hereditary tyrosinaemia

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