Reprogramming metabolic pathways in vivo with CRISPR/Cas9 genome editing to treat hereditary tyrosinaemia
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...
Saved in:
Published in | Nature communications Vol. 7; no. 1; p. 12642 |
---|---|
Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
30.08.2016
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/ncomms12642 |