Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha‐1‐anti‐trypsin deficiency

Autor: Philip Ng, Elena Polishchuk, Nicola Brunetti-Pierri, Simona Iacobacci, Andrea Ballabio, Rosa Maria Sepe, Donna Palmer, Roman S. Polishchuk, Keith Blomenkamp, Nunzia Pastore, Fabio Annunziata, Jeffrey Teckman, Francesco Vetrini, Pasquale Piccolo, Pratibha Mithbaokar
Přispěvatelé: Pastore, N., Blomenkamp, K., Annunziata, Fabio, Piccolo, P., Mithbaokar, P., Sepe, R. M., Vetrini, F., Palmer, D., Ng, P., Polishchuk, P., Iacobacci, S., Polishchuk, R., Teckman, J., Ballabio, A., BRUNETTI PIERRI, Nicola
Rok vydání: 2013
Předmět:
Liver Cirrhosis
Time Factors
Apoptosis
Autophagy-Related Protein 7
Mice
Liver disease
0302 clinical medicine
Gene expression
Research Articles
alpha-1-anti-trypsin
Mice
Knockout
0303 health sciences
Alpha 1-antitrypsin deficiency
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Gene Transfer Techniques
NF-kappa B
gene therapy
3. Good health
Phenotype
Liver
030220 oncology & carcinogenesis
Molecular Medicine
helper-dependent adenoviral vector
Microtubule-Associated Proteins
autophagy
Transgene
Mutation
Missense
Mice
Transgenic
Biology
Transfection
03 medical and health sciences
alpha 1-Antitrypsin Deficiency
medicine
Animals
Humans
Genetic Predisposition to Disease
030304 developmental biology
TFEB
Interleukin-6
Autophagy
Genetic Therapy
medicine.disease
NFKB1
Molecular biology
Mice
Inbred C57BL
Disease Models
Animal
alpha 1-Antitrypsin
Cancer research
Lysosomes
HeLa Cells
Papio
Zdroj: EMBO Molecular Medicine
ISSN: 1757-4684
1757-4676
DOI: 10.1002/emmm.201202046
Popis: 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.
Databáze: OpenAIRE
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