Reprogramming metabolic pathways in vivo with CRISPR/Cas9 genome editing to treat hereditary tyrosinaemia
| Autor: | Diane Yang, Beatrice Bissig-Choisat, Milan Ravishankar, Qin Sun, Sarah H. Elsea, Pavel Sumazin, Karl-Dimiter Bissig, Tian Mi, Francis P. Pankowicz, Mercedes Barzi, Malgorzata Borowiak, Julie A. Tomolonis, Leroy Hubert, Xavier Legras |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Hydrolases Liver cytology Science General Physics and Astronomy Mice Inbred Strains Biology Bioinformatics Article General Biochemistry Genetics and Molecular Biology Cell Line Mice 03 medical and health sciences Genome editing Animals Humans CRISPR Enzyme Inhibitors Gene Cell Proliferation Gene Editing Mice Knockout Multidisciplinary Cyclohexanones Tyrosinemias Cas9 Exons Genetic Therapy General Chemistry Phenotype 3. Good health Disease Models Animal Metabolic pathway 030104 developmental biology Liver Nitrobenzoates Hepatocytes CRISPR-Cas Systems Oxidoreductases Reprogramming Metabolic Networks and Pathways |
| Zdroj: | Nature Communications, Vol 7, Iss 1, Pp 1-6 (2016) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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