Liver tissue: a proof-of-concept study for OLT in MNGIE patients

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an extremely rare autosomal recessive mitochondrial disease due to mutations to the nuclear TYMP gene. Thus, the mechanism which takes place in this condition leads to thymidine phosphorylase (TP) enzyme inactivity (either partial or complete - i.e., virtually lacking) resulting in toxic accumulation of thymidine and therefore altered mitochondrial DNA. MNGIE is characterized by severe gastrointestinal dysmotility, neurological impairment, poor quality of life and reduced life expectancy. Currently, therapeutic options for MNGIE are still limited. In order to restore TP activity, allogenic hematopoietic stem cell transplantation has been used as cellular source of TP although with modest results, the 5-year mortality rate being about 70%. This research tested the hypothesis that the liver can be an alternative source of TP. Eleven patients (7M; 35-55 years) who underwent hepatic resection for focal disorders were included. Margins of normal liver tissue were obtained during surgery and processed to identify, quantify and localize the TP protein by an array of techniques (Western Blot, ELISA, and immunohistochemistry) and to evaluate TYMP mRNA expression by qPCR. Western Blot identified TP in the liver with a TP/GAPDH ratio of 0.9±0.5. ELISA estimated TP content as 0.5±0.07 ng/mg of total protein. TP was identified in both nuclei and cytoplasm of hepatocytes and sinusoidal lining cells. TYMP mRNA was expressed in the liver. In this study, we provided evidence that the liver is an important source of TP. Our experiments represent a proof-of-concept that orthotopic liver transplantation (OLT) can be indicated as possible therapeutic alternative for MNGIE patients.