Using pig model, Mayo Clinic researchers demonstrate the long-term safety and efficacy of hepatocyte-directed gene therapy in treating hereditary tyrosinemia type 1 (HT1), an inborn error of metabolism.
HT1 is an autosomal recessive disorder caused by the deficiency of fumarylacetoacetate hydrolase (FAH). Currently, liver transplantation is the only curative treatment option available for HT1 patients. The success of viral vector-mediated gene therapy in various diseases prompted researchers to test this strategy in animal models of HT1. Further studies have shown the efficacy of ex vivo hepatocyte-directed gene therapy in replacing the defective Fah gene, thus curing liver disease in small animal models of HT1.
In the present study published in Cell Transplantation, Dr Joseph B. Lillegard (Mayo Clinic, USA) and team evaluated the long-term clinical outcome of this therapeutic approach in a pig model of HT1 that they developed earlier. Hepatocytes isolated from Fah-/- pig were transduced with a lentiviral vector expressing porcine Fah. The vector-transduced autologous hepatocytes were transplanted back to the same pig and was examined over the course of three years.
The animal continued to thrive off the protective drug NTBC and the transplanted FAH-positive cells repopulated the liver. Biochemical and histological analysis performed 31 months after transplantation showed that all parameters of liver function and structure were normal, and no evidence of cirrhosis was seen.
Thus, the study provides preclinical evidence for the long-term safety and efficacy of hepatocyte-directed gene therapy in treating HT1 and other metabolic liver diseases. Further studies to address the safety concerns and appropriate dose levels are required before testing this in humans.
Source: Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1. Hickey RD et al., Cell Transplantation, November 2018. DOI