Editing a disease-related gene reverses a metabolic liver disorder in mice
Metabolic liver disorder is a group of diseases in which abnormal chemical reactions in the body disrupt the body's metabolism. For example, Hereditary tyrosinaemia type I (HT-I) is a liver disease that is caused by a deficiency in fumarylacetoacetate hydrolase (FAH)
, which is an enzyme that is important for the breakdown of the animo acid tyrosine. HT-I is characterized by elevated blood levels of tyrosine, and it can lead to liver and kidney failure, and an increased risk of liver cancer. Patients with the condition have to take medicines for a lifetime and may be treated by orthotopic liver transplantation.
Recently, a study from Baylor College of Medicine has revealed that removing a disease-related gene may reverse HT-I in mice, and a one-time treatment is enough. The approach used by the researchers is described as metabolic pathway reprogramming. Dr. Karl-Dimiter Bissig explained that they rewrote the metabolic pathway so the normal processes needed don't have to cross paths with the areas or gene that is causing the disease.
Mutations in the FAH gene that makes the FAH enzyme can lead to a lack of the enzyme. HT-I is caused by an accumulation of toxic catabolic products that result from the loss of the FAH enzyme. In the study, the research team looked at a disease-related gene rather than the disease-causing gene. They deleted a section of DNA from the Hpd gene through CRISPR/Cas9 editing. The liver cells that were edited displayed a growth advantage over those non-edited, and almost completely replaced them within several weeks. This eventually changed tyrosine catabolism, leaving treated mice healthy and asymptomatic. Furthermore, Hpd editing did not influence other cellular pathways.
The approach, metabolic pathway reprogramming, used in this study may also apply to other disorders. The study appears in Nature Communications.