title: Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha-1-anti-trypsin deficiency.
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.
authors: Telethon Institute of Genetics and Medicine, Naples, Italy.
authors: Nunzia
authors: N
authors: Pastore
authors: Keith
authors: K
authors: Blomenkamp
authors: Fabio
authors: F
authors: Annunziata
authors: Pasquale
authors: P
authors: Piccolo
authors: Pratibha
authors: P
authors: Mithbaokar
authors: Rosa
authors: R
authors: Maria Sepe
authors: Francesco
authors: F
authors: Vetrini
authors: Donna
authors: D
authors: Palmer
authors: Philip
authors: P
authors: Ng
authors: Elena
authors: E
authors: Polishchuk
authors: Simona
authors: S
authors: Iacobacci
authors: Roman
authors: R
authors: Polishchuk
authors: Jeffrey
authors: J
authors: Teckman
authors: Andrea
authors: A
authors: Ballabio
authors: Nicola
authors: N
authors: Brunetti-Pierri
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000235:genetics; D000071193:Autophagy-Related Protein 7; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D020022:Genetic Predisposition to Disease; D015316:Genetic Therapy / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism; D010215:Papio; D010641:Phenotype; D013997:Time Factors; D014162:Transfection; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000628:therapy*
chemical_list: C502661:Atg7 protein, mouse; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015850:Interleukin-6; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; C043392:SERPINA1 protein, human; C064972:TFEB protein, human; D000515:alpha 1-Antitrypsin; D000071193:Autophagy-Related Protein 7
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