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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.

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