Abstract
Alpha-1-anti-trypsin deficiency is the most common genetic cause of liver disease in children and liver transplantation is currently the only available treatment. Enhancement of liver autophagy increases degradation of mutant, hepatotoxic alpha-1-anti-trypsin (ATZ). We investigated the therapeutic potential of liver-directed gene transfer of transcription factor EB (TFEB), a master gene that regulates lysosomal function and autophagy, in PiZ transgenic mice, recapitulating the human hepatic disease. Hepatocyte TFEB gene transfer resulted in dramatic reduction of hepatic ATZ, liver apoptosis and fibrosis, which are key features of alpha-1-anti-trypsin deficiency. Correction of the liver phenotype resulted from increased ATZ polymer degradation mediated by enhancement of autophagy flux and reduced ATZ monomer by decreased hepatic NFκB activation and IL-6 that drives ATZ gene expression. In conclusion, TFEB gene transfer is a novel strategy for treatment of liver disease of alpha-1-anti-trypsin deficiency. This study may pave the way towards applications of TFEB gene transfer for treatment of a wide spectrum of human disorders due to intracellular accumulation of toxic proteins.
Highlights
Alpha-1-anti-trypsin (AAT) deficiency is the most common genetic cause of liver disease in children (Perlmutter, 2009; Sveger, 1988)
The results of the present study indicate that helper-dependent adenoviral (HDAd) vectormediated Transcription factor EB (TFEB) hepatic expression resulted in reduction of ATZ aggregates that were already present, prevention of further formation of ATZ globules, and it is effective at reducing liver injury, as shown by decreased hepatic apoptosis and fibrosis (Fig 10)
Liver-directed gene transfer of TFEB, a master gene that regulates lysosomal function and autophagy, in the mouse model of alpha1-anti-trypsin deficiency resulted in reduction of mutant, hepatotoxic alpha-1-anti-trypsin and rescue of liver apoptosis and fibrosis, which are key features of alpha-1-anti-trypsin deficiency
Summary
Alpha-1-anti-trypsin (AAT) deficiency is the most common genetic cause of liver disease in children (Perlmutter, 2009; Sveger, 1988). It is responsible for chronic liver disease and hepatocellular carcinoma in adults (Eriksson et al, 1986; Piitulainen et al, 2005). Strategies are under investigation to overcome this obstacle and recently, a minimally invasive and clinically attractive method for safe and efficient delivery of HDAd vectors to the liver has been developed in preclinical large animal models (BrunettiPierri et al, 2007, 2009b, 2012)
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