| First Author | Pankowicz FP | Year | 2016 |
| Journal | Nat Commun | Volume | 7 |
| Pages | 12642 | PubMed ID | 27572891 |
| Mgi Jnum | J:241908 | Mgi Id | MGI:5903840 |
| Doi | 10.1038/ncomms12642 | Citation | Pankowicz FP, et al. (2016) Reprogramming metabolic pathways in vivo with CRISPR/Cas9 genome editing to treat hereditary tyrosinaemia. Nat Commun 7:12642 |
| abstractText | 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. |
