Liver-directed gene therapy offers hope for tyrosinemia patients

In News by

Mayo clinic scientists demonstrate the potential of an ex vivo gene therapy approach to prevent liver failure and fibrosis in pig models of hereditary tyrosinemia type 1, a rare metabolic liver disease.

Hereditary Tyrosinemia type 1 (HT1) is a rare and severe inherited metabolic disorder, caused by a deficiency in the last enzyme of tyrosine catabolism, fumarylacetoacetate hydrolase (FAH). HT1 results in the accumulation of toxic products in the body which, in turn, cause liver and kidney dysfunction. Most untreated patients die within the first two years of life. The HT1 frequency worldwide is about 1 in 100,000 individuals. Treatment with 2-(2-nitro-4-trifluoromethylbenoyl)-1,3-cyclohexanedione (NTBC) and diet are currently being employed for the management of the disease. Liver transplantation is the only cure for the disease. However, the shortage of liver donors calls for the importance of developing alternate strategies to treat HT1.

In the current study published in Science Translational Medicine, a collaborative research led by Dr. Scott L. Nyberg investigated the potential of ex vivo hepatocyte gene therapy in treating HT1. FAH deficient pigs (Fah-/-) were used in the study. Hepatocytes were isolated from Fah-/- pigs and transduced with a lentiviral vector expressing the therapeutic Fah. The animals received autologous transplants of hepatocytes by portal vein infusion. NTBC was withheld from recipient pigs following transplantation to selectively expand FAH+ cells. Results showed that transplantation of gene-corrected cells ex vivo in Fah-/- pigs induced near-complete liver regeneration. Levels of the metabolites, tyrosine and succinylacetone, improved to within the normal range indicating complete correction of tyrosine metabolism. Also, the onset of fibrosis was inhibited after hepatocyte transplantation in Fah-/- pigs.

Thus, the study shows the potential of ex vivo gene therapy in correcting HT1 in pigs. Further investigation of engineered hepatocytes ex vivo is required before this approach can be translated into clinic.

Source: Curative ex vivo liver-directed gene therapy in a pig model of hereditary tyrosinemia type 1. Hickey RD et al., Science Translational Medicine July 2016. DOI