Author
Listed:
- Francis P. Pankowicz
(Center for Cell and Gene Therapy, Baylor College of Medicine
Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine
Graduate Program, Baylor College of Medicine)
- Mercedes Barzi
(Center for Cell and Gene Therapy, Baylor College of Medicine
Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine)
- Xavier Legras
(Center for Cell and Gene Therapy, Baylor College of Medicine
Center for Stem Cells and Regenerative Medicine, 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
Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine)
- Qin Sun
(Baylor College of Medicine)
- Diane Yang
(Center for Cell and Gene Therapy, Baylor College of Medicine
Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine
Graduate Program, Baylor College of Medicine
McNair Medical Institute)
- Malgorzata Borowiak
(Center for Cell and Gene Therapy, Baylor College of Medicine
Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine
Graduate Program, Baylor College of Medicine
Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine)
- Pavel Sumazin
(Texas Children’s Hospital
Dan L. Duncan Cancer Center, Baylor College of Medicine)
- Sarah H. Elsea
(Baylor College of Medicine)
- Beatrice Bissig-Choisat
(Center for Cell and Gene Therapy, Baylor College of Medicine
Baylor College of Medicine)
- Karl-Dimiter Bissig
(Center for Cell and Gene Therapy, Baylor College of Medicine
Center for Stem Cells and Regenerative Medicine, Baylor College of Medicine
Graduate Program, Baylor College of Medicine
Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine)
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.
Suggested Citation
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 & , 2016.
"Reprogramming metabolic pathways in vivo with CRISPR/Cas9 genome editing to treat hereditary tyrosinaemia,"
Nature Communications, Nature, vol. 7(1), pages 1-6, November.
Handle:
RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12642
DOI: 10.1038/ncomms12642
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Cited by:
- Clara T. Nicolas & Caitlin J. VanLith & Raymond D. Hickey & Zeji Du & Lori G. Hillin & Rebekah M. Guthman & William J. Cao & Benjamin Haugo & Annika Lillegard & Diya Roy & Aditya Bhagwate & Daniel O’B, 2022.
"In vivo lentiviral vector gene therapy to cure hereditary tyrosinemia type 1 and prevent development of precancerous and cancerous lesions,"
Nature Communications, Nature, vol. 13(1), pages 1-15, December.
- Raed Ibraheim & Phillip W. L. Tai & Aamir Mir & Nida Javeed & Jiaming Wang & Tomás C. Rodríguez & Suk Namkung & Samantha Nelson & Eraj Shafiq Khokhar & Esther Mintzer & Stacy Maitland & Zexiang Chen &, 2021.
"Self-inactivating, all-in-one AAV vectors for precision Cas9 genome editing via homology-directed repair in vivo,"
Nature Communications, Nature, vol. 12(1), pages 1-17, December.
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