Abstract
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.
Highlights
Many metabolic liver disorders are refractory to drug therapy and require orthotopic liver transplantation
Since 1992, patients have been treated with nitisinone[2], which inhibits the second step of tyrosine catabolism, hydroxyphenylpyruvate dioxigenase (HPD)
Fah À / À mice treated with nitisinone suffer an increased risk of hepatocellular carcinoma, but this risk disappears when the mice are crossed with Hpd À / À (HT-III) mice[16]
Summary
Many metabolic liver disorders are refractory to drug therapy and require orthotopic liver transplantation. Since 1992, patients have been treated with nitisinone[2], which inhibits the second step of tyrosine catabolism, hydroxyphenylpyruvate dioxigenase (HPD) This pharmacological block is incomplete, so that nitisinone treatment reduces the risk of HT-I patients developing hepatocellular carcinoma, the incidence of this cancer is still significantly greater in this population[14,15]. We hypothesized that a genetic deletion of Hpd in the liver using CRISPR/Cas[9] technology might be a more efficient therapy than an incomplete pharmacological block by nitisinone. This strategy of genetically blocking a gene other than the diseased gene as a treatment is the core of metabolic pathway reprogramming.
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