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 and Karl-Dimiter Bissig ()
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Francis P. Pankowicz: Center for Cell and Gene Therapy, Baylor College of Medicine
Mercedes Barzi: Center for Cell and Gene Therapy, Baylor College of Medicine
Xavier Legras: Center for Cell and Gene Therapy, Baylor College of Medicine
Leroy Hubert: Baylor College of Medicine
Tian Mi: Texas Children’s Hospital
Julie A. Tomolonis: Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine
Milan Ravishankar: Center for Cell and Gene Therapy, Baylor College of Medicine
Qin Sun: Baylor College of Medicine
Diane Yang: Center for Cell and Gene Therapy, Baylor College of Medicine
Malgorzata Borowiak: Center for Cell and Gene Therapy, Baylor College of Medicine
Pavel Sumazin: Texas Children’s Hospital
Sarah H. Elsea: Baylor College of Medicine
Beatrice Bissig-Choisat: Center for Cell and Gene Therapy, Baylor College of Medicine
Karl-Dimiter Bissig: Center for Cell and Gene Therapy, Baylor College of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-6

Abstract: Abstract Many 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.

Date: 2016
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DOI: 10.1038/ncomms12642

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