Journal Article

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

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

2016

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 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 / Liver transplantation / 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