title: Update on alpha-1 antitrypsin deficiency: New therapies.
abstract: 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 25years 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.
authors.affiliation: UCL Respiratory, Division of Medicine, Rayne Building, University College London, UK; The London Alpha-1-Antitrypsin Deficiency Service, Royal Free London NHS Foundation Trust, London, UK; Institute of Structural and Molecular Biology, UCL/Birkbeck College, University of London, London WC1E 7HX, UK. Electronic address: d.lomas@ucl.ac.uk.
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.affiliation: UCL Respiratory, Division of Medicine, Rayne Building, University College London, UK; The London Alpha-1-Antitrypsin Deficiency Service, Royal Free London NHS Foundation Trust, London, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Hurst
authors.affiliation: The London Alpha-1-Antitrypsin Deficiency Service, Royal Free London NHS Foundation Trust, London, UK; Institute of Structural and Molecular Biology, UCL/Birkbeck College, University of London, London WC1E 7HX, UK; Division of Asthma, Allergy and Lung Biology, King's College London, Guy's Hospital, 5th Floor, Tower Wing, London, UK.
authors.forename: Bibek
authors.initials: B
authors.lastname: Gooptu
mesh_terms: D000818:Animals; D006801:Humans; D000515:alpha 1-Antitrypsin; D019896:alpha 1-Antitrypsin Deficiency
chemical_list: D000515:alpha 1-Antitrypsin
keywords: Cirrhosis; Emphysema; Polymerisation; Serpins; Therapeutic strategies