α1-Antitrypsin deficiency (A1ATD) is an inherited disorder caused by mutations in SERPINA1, leading to liver and lung disease. It is not a rare disorder but frequently goes underdiagnosed or misdiagnosed as asthma, chronic obstructive pulmonary disease (COPD) or cryptogenic liver disease. The most frequent disease-associated mutations include the S allele and the Z allele of SERPINA1, which lead to the accumulation of misfolded α1-antitrypsin in hepatocytes, endoplasmic reticulum stress, low circulating levels of α1-antitrypsin and liver disease. Currently, there is no cure for severe liver disease and the only management option is liver transplantation when liver failure is life-threatening. A1ATD-associated lung disease predominately occurs in adults and is caused principally by inadequate protease inhibition. Treatment of A1ATD-associated lung disease includes standard therapies that are also used for the treatment of COPD, in addition to the use of augmentation therapy (that is, infusions of human plasma-derived, purified α1-antitrypsin). New therapies that target the misfolded α1-antitrypsin or attempt to correct the underlying genetic mutation are currently under development.
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Funding for research in C.M.G.'s group is gratefully acknowledged from the Health Research Board, Science Foundation Ireland, the Irish Research Council, the National Children's Research Centre, the European Respiratory Society, Horizon 2020, Cystic Fibrosis Foundation Therapeutics and the Alpha One Foundation USA. The authors thank J. Irving, University College London (UCL), UK, for preparing the crystal structures used in Figure 3.
C.M.G. has received research grants from the Alpha-1 Foundation and received an honorarium for educational materials from Vertex Pharmaceuticals. J.T. has served as a consultant for Alnylam Pharmaceuticals, Arrowhead Research, Proteostasis Therapeutics, Isis Pharmaceuticals (now Ionis Pharmaceuticals), Editas Medicine, Genkyotex, GLG Pharma, INSERM, Intellia Therapeutics, Retrophin, RxCelerate and Velgene. He also received honoraria for speaking from the Alpha-1 Foundation and the Cystic Fibrosis Foundation and research grants or support from the Alpha-1 Foundation, US NIH, Alnylam Pharmaceuticals, Arrowhead Research and the Cardinal Glennon Children's Foundation. M.L.B. has received research support for clinical trials from Baxalta, Kamada and Grifols, is an owner of GeneAidyx, a genetic diagnostic company, and holds patents for α1-antitrypsin gene therapy and compounds to modify α1-antitrypsin secretion. D.A.L. has received research funding from GlaxoSmithKline to develop small-molecule therapies for α1-antitrypsin deficiency. He was also chair of the GlaxoSmithKline Respiratory Therapy Area Board between 2012 and 2015. J.K.S. has served as a consultant for Kamada, Grifols, Arrowhead Research, CSL Behring, Baxalta, Pfizer and Boehringer-Ingelheim. He is a member of the board of directors of the Alpha-1 Foundation, and the Medical and Scientific Advisory Council for both the COPD Foundation and the Alpha-1 Foundation. N.G.M. has served as a consultant for Chiesi and Bayer and received honoraria for speaking from Chiesi, Grifols and CSL Behring. He also received grants or research support from Chiesi, Grifols, Vertex and the Alpha-1 Foundation. S.J.M. and I.F. declare no competing interests.
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Greene, C., Marciniak, S., Teckman, J. et al. α1-Antitrypsin deficiency. Nat Rev Dis Primers 2, 16051 (2016). https://doi.org/10.1038/nrdp.2016.51
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