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Semin Liver Dis 2017; 37(02): 152-158
DOI: 10.1055/s-0037-1602586
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Emerging Concepts and Human Trials in Alpha-1-Antitrypsin Deficiency Liver Disease

Jeffrey H. Teckman
1   Department of Pediatrics and Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri
2   Department of Pediatric Gastroenterology and Hepatology, Cardinal Glennon Children's Hospital, Saint Louis, Missouri
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Publication History

Publication Date:
31 May 2017 (online)

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Abstract

In α-1-antitrypsin (AAT) deficiency, individuals homozygous for the AAT mutant Z gene synthesize large quantities of mutant Z protein in the liver, which folds improperly during biogenesis and is retained within the hepatocytes rather than appropriated secreted. This accumulation of mutant Z protein triggers an intracellular injury cascade causing cell death in the population of hepatocytes with the largest accumulations of Z protein. Hepatocellular proliferation, hepatic fibrosis, and hepatocellular cancer in some individuals can be the result. New insights from basic science studies have now allowed the application of new biotechnologies to this previously untreatable disease. Specifically, drugs designed to accelerate the intracellular removal of the mutant Z protein (autophagy enhancers) and siRNA strategies designed to shut down synthesis of the toxic, mutant Z protein, are now in human trials. Other approaches, such as gene correction, cell therapy, and antifibrotic drugs are in preclinical development.

Keywords

alpha-1-antitrypsin - autophagy - liver disease - siRNA - endoplasmic reticulum-associated degradation
 

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