Targeting intracellular degradation pathways for treatment of liver disease caused by α1-antitrypsin deficiency.
The classic form of α1-antitrypsin deficiency (ATD) is a well-known genetic cause of severe liver disease in childhood. A point mutation alters the folding of a hepatic secretory glycoprotein such that the protein is prone to misfolding and polymerization. Liver injury, characterized predominantly by fibrosis/cirrhosis and carcinogenesis, is caused by the proteotoxic effect of polymerized mutant α1-antitrypsin Z (ATZ), which accumulates in the endoplasmic reticulum (ER) of hepatocytes. Several intracellular pathways have been shown to be responsible for disposal of ATZ after it accumulates in the ER, but autophagy appears to be specialized for disposal of insoluble ATZ polymers. Recently, we have found that drugs that enhance the activity of the autophagic pathway reduce the cellular load of mutant ATZ and reverse hepatic fibrosis in a mouse model of ATD. Because several of these autophagy enhancers have been used safely in humans for other reasons, we have been able to initiate a clinical trial of one of these drugs, carbamazepine, to determine its efficacy in severe liver disease due to ATD. In this review, we discuss the autophagy enhancer drugs as a new therapeutic strategy that targets cell biological mechanisms integral to the pathogenesis of liver disease due to ATD.
1] Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania [2] Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Yan
Y
Wang
1] Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania [2] Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania [3] Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
David H
DH
Perlmutter
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002220:Carbamazepine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D055808:Drug Discovery; D020022:Genetic Predisposition to Disease; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D058990:Molecular Targeted Therapy; D010641:Phenotype; D017354:Point Mutation; D059748:Proteolysis / Q000187:drug effects*; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology
C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D002220:Carbamazepine