Update on alpha-1 antitrypsin deficiency: New therapies

Summary α1 -Antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1 -antitrypsin within the endoplasmic reticulum of hepatocytes. The retention of mutant protein causes hepatic damage and cirrhosis whilst the lack of an important circulating protease inhibitor predisposes the individuals with severe α1 -antitrypsin deficiency to early onset emphysema. Our work over the past 25 years has led to new paradigms for the liver and lung disease associated with α1 -antitrypsin deficiency. We review here the molecular pathology of the cirrhosis and emphysema associated with α1 -antitrypsin deficiency and show how an understanding of this condition provided the paradigm for a wider group of disorders that we have termed the serpinopathies. The detailed understanding of the pathobiology of α1 -antitrypsin deficiency has identified important disease mechanisms to target. As a result, several novel parallel and complementary therapeutic approaches are in development with some now in clinical trials. We provide an overview of these new therapies for the liver and lung disease associated with α1 -antitrypsin deficiency.