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

• Published in: Nature communications Vol. 7; no. 1; p. 12642
• Main Authors: Pankowicz, Francis P., Barzi, Mercedes, Legras, Xavier, Hubert, Leroy, Mi, Tian, Tomolonis, Julie A., Ravishankar, Milan, Sun, Qin, Yang, Diane, Borowiak, Malgorzata, Sumazin, Pavel, Elsea, Sarah H., Bissig-Choisat, Beatrice, Bissig, Karl-Dimiter
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.08.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 42/41; 631/337/4041; 631/61/318; 692/699/1503/1607; Animals; Cell cycle; Cell Line; Cell Proliferation - genetics; Cellular biology; CRISPR; CRISPR-Cas Systems - genetics; Cyclohexanones - therapeutic use; Disease Models, Animal; Drug therapy; Enzyme Inhibitors - therapeutic use; Enzymes; Exons - genetics; Gene Editing - methods; Genetic Therapy - methods; Genomes; Hepatocytes - metabolism; Humanities and Social Sciences; Humans; Hydrolases - genetics; Liver - cytology; Liver - pathology; Liver cancer; Liver diseases; Medical schools; Medicine; Metabolic Networks and Pathways - genetics; Metabolism; Mice; Mice, Inbred Strains; Mice, Knockout; multidisciplinary; Nitrobenzoates - therapeutic use; Oxidoreductases - antagonists & inhibitors; Oxidoreductases - genetics; Oxidoreductases - metabolism; Phenotype; Science; Science (multidisciplinary); Tyrosinemias - genetics; Tyrosinemias - metabolism; Tyrosinemias - pathology; Tyrosinemias - therapy; United States > US; Texas
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12642

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. Hereditary tyrosinaemia type I is caused by a gene defect that leads to a lethal accumulation of toxic metabolites in the liver. Here the authors use CRISPR/Cas9 to 'cure' the disease in mice by inactivating another gene, rather than targeting the disease-causing gene itself, to reroute hepatic tyrosine catabolism.