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.

TFEB at a glance

“…TFEB overexpression has also shown therapeutic effects in mouse models of α1-antitrypsin deficiency, the most common genetic cause of liver disease (Pastore et al, 2013). In this case as well, enhanced intracellular clearance represents the major therapeutic mechanism, as induction of autophagy by TFEB reduces the levels of α1-antitrypsin accumulation and ameliorates liver injury.…”

Transcriptional regulation of mammalian autophagy at a glance

“…For instance, overexpression of TFEB rescues toxicity of α-synuclein and protects dopaminergic neurons in a rat model of Parkinson's disease that is induced by viral overexpression of α-synuclein (Decressac et al, 2013); it also ameliorates toxicity by enhancing the clearance of misfolded polyglutamine-expanded ( polyQ) huntingtin protein (Tsunemi et al, 2012) and the mutant androgen receptor that causes X-linked spinal and bulbar muscular atrophy (Cortes et al, 2014). Gene transfer of TFEB alleviates pathology in a mouse model of alpha-1-anti-trypsin deficiency (Pastore et al, 2013). Moreover, activation of autophagy and lysosomal activity by TFEB attenuates the pathological phenotype in mouse models of Pompe disease (Spampanato et al, 2013).…”

Autophagy and gene therapy combine in the treatment of liver disease

“…9 The problem of applying gene therapy to treat diseases associated with protein misfolding and aggregation has now been addressed, in part, by a study concerning liver disease. 10 Andrea Ballabio and colleagues previously described the coordinated lysosomal expression and regulation (CLEAR) network, 11 which is controlled through the transcription factor TFEB, and demonstrated that it regulates macroautophagy in an MTOR-dependent manner. [12][13][14] The possibility of manipulating TFEB to treat a disease by upregulating macroautophagy was seen with the finding that overexpression of TFEB, or its upstream regulator PPARGC1A/ PGC-1α, rescues the neurodegenerative effects resulting from HTT toxicity.…”

“…15 Now, a paper from Nicola BrunettiPierri and colleagues has advanced this knowledge by using TFEB-based gene therapy to treat a mouse model of α 1 -antitrypsin deficiency. 10 In this disease, a mutant form of SERPINA1/A1AT accumulates in particular in liver cells, the site of its synthesis, and can lead to cirrhosis. In addition, a deficiency of SERPIN1A in the lungs can lead to emphysema.…”

“…16,17 Of course, there are problems associated with the long-term use of systemic drugs. Hence, this is one reason why the study by Pastore et al 10,18 holds great promise. In this case, the authors relied on overexpression of liver-directed TFEB to upregulate macroautophagy and promote clearance of the altered SERPIN1A protein, suppressing the disease phenotype.…”