Advertisement

Update on alpha-1 antitrypsin deficiency: New therapies

  • David A. Lomas
    Correspondence
    Corresponding author. Address: UCL Respiratory, Division of Medicine, Rayne Building, University College London WC1E 6JF, UK. Tel.: +44 020 7679 6503.
    Affiliations
    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
    Search for articles by this author
  • John R. Hurst
    Affiliations
    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
    Search for articles by this author
  • Bibek Gooptu
    Affiliations
    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
    Search for articles by this author
Published:March 28, 2016DOI:https://doi.org/10.1016/j.jhep.2016.03.010

      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.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Lomas D.A.
        • Mahadeva R.
        Alpha-1-antitrypsin polymerisation and the serpinopathies: pathobiology and prospects for therapy.
        J Clin Invest. 2002; 110: 1585-1590
        • Lomas D.A.
        • Evans D.L.
        • Finch J.T.
        • Carrell R.W.
        The mechanism of Z α1-antitrypsin accumulation in the liver.
        Nature. 1992; 357: 605-607
        • Sveger T.
        Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants.
        N Engl J Med. 1976; 294: 1316-1321
        • Eriksson S.
        • Carlson J.
        • Velez R.
        Risk of cirrhosis and primary liver cancer in alpha1-antitrypsin deficiency.
        N Engl J Med. 1986; 314: 736-739
        • Dawwas M.F.
        • Davies S.E.
        • Griffiths W.J.
        • Lomas D.A.
        • Alexander G.J.
        Prevalence and risk factors for liver involvement in individuals with PiZZ-related lung disease.
        Am J Respir Crit Care Med. 2013; 187: 502-508
        • Eriksson S.
        Studies in α1-antitrypsin deficiency.
        Acta Med Scand. 1965; 432: 1-85
        • Miranda E.
        • Pérez J.
        • Ekeowa U.I.
        • Hadzic N.
        • Kalsheker N.
        • Gooptu B.
        • et al.
        A novel monoclonal antibody to characterise pathogenic polymers in liver disease associated with α1-antitrypsin deficiency.
        Hepatology. 2010; 52: 1078-1088
        • Dafforn T.R.
        • Mahadeva R.
        • Elliott P.R.
        • Sivasothy P.
        • Lomas D.A.
        A kinetic mechanism for the polymerisation of α1-antitrypsin.
        J Biol Chem. 1999; 274: 9548-9555
        • Gooptu B.
        • Hazes B.
        • Chang W.-S.W.
        • Dafforn T.R.
        • Carrell R.W.
        • Read R.
        • et al.
        Inactive conformation of the serpin α1-antichymotrypsin indicates two stage insertion of the reactive loop; implications for inhibitory function and conformational disease.
        Proc Natl Acad Sci U S A. 2000; 97: 67-72
        • Haq I.
        • Irving J.A.
        • Faull S.V.
        • Dickens J.A.
        • Ordóñez A.
        • Belorgey D.
        • et al.
        Reactive centre loop mutants of α-1-antitrypsin reveal position-specific effects on intermediate formation along the polymerization pathway.
        Biosci Rep. 2013; 33e00046
        • Irving J.A.
        • Haq I.
        • Dickens J.A.
        • Faull S.V.
        • Lomas D.A.
        Altered native stability is the dominant basis for susceptibility of α1-antitrypsin mutants to polymerization.
        Biochem J. 2014; 460: 103-115
        • Haq I.
        • Irving J.A.
        • Saleh A.D.
        • Dron L.
        • Regan-Mochrie G.L.
        • Motamedi-Shad N.
        • et al.
        Deficiency mutations of alpha-1 antitrypsin. Effects on folding, function, and polymerization.
        Am J Respir Cell Mol Biol. 2016; 54: 71-80
        • Gooptu B.
        • Miranda E.
        • Nobeli I.
        • Mallya M.
        • Purkiss A.
        • Leigh Brown S.C.
        • et al.
        Crystallographic and cellular characterisation of two mechanisms stabilising the native fold of alpha-1-antitrypsin: implications for disease and drug design.
        J Mol Biol. 2009; 387: 857-868
        • Nyon M.P.
        • Segu L.
        • Cabrita L.D.
        • Lévy G.R.
        • Kirkpatrick J.
        • Roussel B.D.
        • et al.
        Structural dynamics associated with intermediate formation in an archetypal conformational disease.
        Structure. 2012; 20: 504-512
        • Ekeowa U.I.
        • Freekeb J.
        • Miranda E.
        • Gooptu B.
        • Bush M.F.
        • Pérez J.
        • et al.
        Defining the mechanism of polymerization in the serpinopathies.
        Proc Natl Acad Sci U S A. 2010; 107: 17146-17151
        • Nyon M.P.
        • Prentice T.
        • Day J.
        • Kirkpatrick J.
        • Sivalingam G.N.
        • Levy G.
        • et al.
        An integrative approach combining ion mobility mass spectrometry, X-ray crystallography and NMR spectroscopy to study the conformational dynamics of α1-antitrypsin upon ligand binding.
        Protein Sci. 2015; 24: 1301-1312
        • Lomas D.A.
        • Finch J.T.
        • Seyama K.
        • Nukiwa T.
        • Carrell R.W.
        α1-antitrypsin Siiyama (Ser53 -->Phe); further evidence for intracellular loop-sheet polymerisation.
        J Biol Chem. 1993; 268: 15333-15335
        • Lomas D.A.
        • Elliott P.R.
        • Sidhar S.K.
        • Foreman R.C.
        • Finch J.T.
        • Cox D.W.
        • et al.
        Alpha1-antitrypsin Mmalton (52Phe deleted) forms loop-sheet polymers in vivo: evidence for the C sheet mechanism of polymerisation.
        J Biol Chem. 1995; 270: 16864-16870
        • Elliott P.R.
        • Stein P.E.
        • Bilton D.
        • Carrell R.W.
        • Lomas D.A.
        Structural explanation for the dysfunction of S α1-antitrypsin.
        Nat Struct Biol. 1996; 3: 910-911
        • Mahadeva R.
        • Chang W.-S.W.
        • Dafforn T.R.
        • Oakley D.J.
        • Foreman R.C.
        • Calvin J.
        • et al.
        Heteropolymerisation of S, I and Z α1-antitrypsin and liver cirrhosis.
        J Clin Invest. 1999; 103: 999-1006
        • Knaupp A.S.
        • Levina V.
        • Robertson A.L.
        • Pearce M.C.
        • Bottomley S.P.
        Kinetic instability of the serpin Z α1-antitrypsin promotes aggregation.
        J Mol Biol. 2010; 396: 375-383
        • Nyon M.P.
        • Gooptu B.
        Therapeutic targeting of misfolding and conformational change in α1-antitrypsin deficiency.
        Future Med Chem. 2014; 6: 1047-1065
        • Van Goor F.
        • Hadida S.
        • Grootenhuis P.D.
        • Burton B.
        • Cao D.
        • Neuberger T.
        • et al.
        Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770.
        Proc Natl Acad Sci U S A. 2009; 106: 18825-18830
        • Van Goor F.
        • Hadida S.
        • Grootenhuis P.D.
        • Burton B.
        • Stack J.H.
        • Straley K.S.
        • et al.
        Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809.
        Proc Natl Acad Sci U S A. 2011; 108: 18843-18848
        • Yamasaki M.
        • Li W.
        • Johnson D.J.
        • Huntington J.A.
        Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization.
        Nature. 2008; 455: 1255-1258
        • Krishnan B.
        • Gierasch L.M.
        Dynamic local unfolding in the serpin α-1 antitrypsin provides a mechanism for loop insertion and polymerization.
        Nat Struct Mol Biol. 2011; 18: 222-226
        • Tsutsui Y.
        • Dela Cruz R.
        • Wintrode P.L.
        Folding mechanism of the metastable serpin α1-antitrypsin.
        Proc Natl Acad Sci U S A. 2012; 109: 4467-4472
        • Yamasaki M.
        • Sendall T.J.
        • Pearce M.C.
        • Whisstock J.C.
        • Huntington J.A.
        Molecular basis of α1-antitrypsin deficiency revealed by the structure of a domain-swapped trimer.
        EMBO Rep. 2011; 12: 1011-1017
        • Behrens M.A.
        • Sendall T.J.
        • Pedersen J.S.
        • Kjeldgaard M.
        • Huntington J.A.
        • Jensen J.K.
        The shapes of Z-α1-antitrypsin polymers in solution support the C-terminal domain-swap mechanism of polymerization.
        Biophysical J. 2014; 107: 1905-1912
        • Kröger H.
        • Miranda E.
        • MacLeod I.
        • Pérez J.
        • Crowther D.C.
        • Marciniak S.J.
        • et al.
        Endoplasmic reticulum-associated degradation (ERAD) and autophagy cooperate to degrade polymerogenic mutant serpins.
        J Biol Chem. 2009; 284: 22793-22802
        • Teckman J.H.
        • Perlmutter D.H.
        Retention of mutant α1-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response.
        Am J Physiol Gastrointest Liver Physiol. 2000; 279: G961-G974
        • Hidvegi T.
        • Mirnics K.
        • Hale P.
        • Ewing M.
        • Beckett C.
        • Perlmutter D.H.
        Regulator of G signaling 16 is a marker for the distinct ER stress state associated with aggregated mutant alpha 1-antitrypsin Z in the classical form of α1-antitrypsin deficiency.
        J Biol Chem. 2007; 282: 27769-27780
        • Ordóñez A.
        • Snapp E.L.
        • Tan L.
        • Miranda E.
        • Marciniak S.J.
        • Lomas D.A.
        Endoplasmic reticulum polymers impair luminal protein mobility and sensitize to cellular stress in alpha-1-antitrypsin deficiency.
        Hepatology. 2013; 57: 2049-2060
        • Lawless M.W.
        • Greene C.M.
        • Mulgrew A.
        • Taggert C.C.
        • O’Neill S.J.
        • McElvaney N.G.
        Activation of endoplasmic reticulum-specific stress responses associated with the conformational disease Z α1-antitrypsin deficiency.
        J Immunol. 2004; 172: 5722-5726
        • Davies M.J.
        • Miranda E.
        • Roussel B.D.
        • Kaufman R.J.
        • Marciniak S.J.
        • Lomas D.A.
        Neuroserpin polymers activate NF-kB by a calcium signalling pathway that is independent of the unfolded protein response.
        J Biol Chem. 2009; 284: 18202-18209
        • Fregonese L.
        • Stolk J.
        • Frants R.R.
        • Veldhuisen B.
        Alpha-1 antitrypsin Null mutations and severity of emphysema.
        Respir Med. 2008; 102: 876-884
        • Turino G.M.
        • Barker A.F.
        • Brantly M.L.
        • Cohen A.B.
        • Connelly R.P.
        • Crystal R.G.
        • et al.
        Clinical features of individuals with PI∗SZ phenotype of α1-antitrypsin deficiency.
        Am J Respir Crit Care Med. 1996; 154: 1718-1725
        • Seersholm N.
        • Kok-Jensen A.
        Intermediate alpha 1-antitrypsin deficiency PiSZ: a risk factor for pulmonary emphysema?.
        Respir Med. 1998; 92: 241-245
        • Elliott P.R.
        • Bilton D.
        • Lomas D.A.
        Lung polymers in Z α1-antitrypsin related emphysema.
        Am J Respir Cell Mol Biol. 1998; 18: 670-674
        • Mulgrew A.T.
        • Taggart C.C.
        • Lawless M.W.
        • Greene C.M.
        • Brantly M.L.
        • O’Neill S.J.
        • et al.
        Z α1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant.
        Chest. 2004; 125: 1952-1957
        • van’t Wout E.F.
        • Dickens J.A.
        • van Schadewijk A.
        • Haq I.
        • Kwok H.F.
        • Ordóñez A
        • et al.
        Increased ERK signalling promotes inflammatory signalling in primary airway epithelial cells expressing Z α1-antitrypsin.
        Hum Mol Genet. 2014; 23: 929-941
        • Mahadeva R.
        • Atkinson C.
        • Li J.
        • Stewart S.
        • Janciauskiene S.
        • Kelley D.G.
        • et al.
        Polymers of Z α1-antitrypsin co-localise with neutrophils in emphysematous alveoli and are chemotactic in vivo.
        Am J Pathol. 2005; 166: 377-386
        • Alam S.
        • Li Z.
        • Janciauskiene S.
        • Mahadeva R.
        Oxidation of Z alpha-1-antitrypsin by cigarette smoke induces polymerization: a novel mechanism of early-onset emphysema.
        Am J Respir Cell Mol Biol. 2011; 45: 261-269
        • Parmar J.S.
        • Mahadeva R.
        • Reed B.J.
        • Farahi N.
        • Cadwallader K.
        • Bilton D.
        • et al.
        Polymers of α1-antitrypsin are chemotactic for human neutrophils: a new paradigm for the pathogenesis of emphysema.
        Am J Respir Cell Mol Biol. 2002; 26: 723-730
        • Tan L.
        • Dickens J.A.
        • Demeo D.L.
        • Miranda E.
        • Perez J.
        • Rashid S.T.
        • et al.
        Circulating polymers in α1-antitrypsin deficiency.
        Eur Respir J. 2014; 43: 1501-1504
        • Gooptu B.
        • Lomas D.A.
        Conformational pathology of the serpins - themes, variations and therapeutic strategies.
        Annu Rev Biochem. 2009; 78: 147-176
        • Davis R.L.
        • Shrimpton A.E.
        • Holohan P.D.
        • Bradshaw C.
        • Feiglin D.
        • Sonderegger P.
        • et al.
        Familial dementia caused by polymerisation of mutant neuroserpin.
        Nature. 1999; 401: 376-379
        • Davis R.L.
        • Shrimpton A.E.
        • Carrell R.W.
        • Lomas D.A.
        • Gerhard L.
        • Baumann B.
        • et al.
        Association between conformational mutations in neuroserpin and onset and severity of dementia.
        Lancet. 2002; 359: 2242-2247
        • Coutelier M.
        • Andries S.
        • Ghariani S.
        • Dan B.
        • Duyckaerts C.
        • van Rijckevorsel K.
        • et al.
        Neuroserpin mutation causes electrical status epilepticus of slow-wave sleep.
        Neurology. 2008; 71: 64-66
        • Hagen M.
        • Murrell J.R.
        • Delisle M.B.
        • Andermann E.
        • Andermann F.
        • Guiot M.C.
        • et al.
        Encephalopathy with neuroserpin inclusion bodies presenting as progressive myoclonus epilepsy and associated with a novel mutation in the proteinase inhibitor 12 Gene.
        Brain Pathol. 2011; 21: 575-582
        • Belorgey D.
        • Crowther D.C.
        • Mahadeva R.
        • Lomas D.A.
        Mutant neuroserpin (Ser49Pro) that causes the familial dementia FENIB is a poor proteinase inhibitor and readily forms polymers in vitro.
        J Biol Chem. 2002; 277: 17367-17373
        • Miranda E.
        • Römisch K.
        • Lomas D.A.
        Mutants of neuroserpin that cause dementia accumulate as polymers within the endoplasmic reticulum.
        J Biol Chem. 2004; 279: 28283-28291
        • Belorgey D.
        • Sharp L.K.
        • Crowther D.C.
        • Onda M.
        • Johansson J.
        • Lomas D.A.
        Neuroserpin Portland (Ser52Arg) is trapped as an inactive intermediate that rapidly forms polymers: implications for the epilepsy seen in the dementia FENIB.
        Eur J Biochem. 2004; 271: 3360-3367
        • Miranda E.
        • McLeod I.
        • Davies M.J.
        • Pérez J.
        • Römisch K.
        • Crowther D.C.
        • et al.
        The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB.
        Hum Mol Genet. 2008; 17: 1527-1539
        • Takehara S.
        • Onda M.
        • Zhang J.
        • Nishiyama M.
        • Yang X.
        • Mikami B.
        • et al.
        The 2.1-A crystal structure of native neuroserpin reveals unique structural elements that contribute to conformational instability.
        J Mol Biol. 2009; 388: 11-20
        • Belorgey D.
        • Hägglöf P.
        • Onda M.
        • Lomas D.A.
        PH dependent stability of neuroserpin is mediated by Histidines 119 and 138; implications for the control of β-sheet A and polymerisation.
        Protein Sci. 2010; 19: 220-228
        • Schipanski A.
        • Lange S.
        • Segref A.
        • Gutschmidt A.
        • Lomas D.A.
        • Miranda E.
        • et al.
        A novel interaction between aging and ER overload in a protein conformational dementia.
        Genetics. 2013; 193: 865-876
        • Gooptu B.
        • Lomas D.A.
        Polymers and inflammation: disease mechanisms of the serpinopathies.
        J Exp Med. 2008; 205: 1529-1534
        • Gooptu B.
        • Dickens J.A.
        • Lomas D.A.
        The molecular and cellular pathology of α1-antitrypsin deficiency.
        Trends Mol Med. 2014; 20: 116-127
        • Mayer N.S.
        • Stoller J.K.
        • Bartelson B.B.
        • Ruttenber A.J.
        • Sandhaus R.A.
        • Newman L.S.
        Occupational exposure risks in Individuals with PI∗Z α1-antitrypsin deficiency.
        Am J Respir Crit Care Med. 2000; 162: 553-558
        • Stoller J.K.
        • Aboussouan L.S.
        Alpha-1 antitrypsin deficiency.
        Lancet. 2005; 365: 2225-2236
        • Dirksen A.
        • Dijkman J.H.
        • Madsen F.
        • Stoel B.
        • Hutchison D.C.S.
        • Ulrik C.S.
        • et al.
        A randomised clinical trial of α1-antitrypsin augmentation therapy.
        Am J Respir Crit Care Med. 1999; 160: 1468-1472
        • Dirksen A.
        • Piitulainen E.
        • Parr D.G.
        • Deng C.
        • Wencker M.
        • Shaker S.B.
        • et al.
        Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency.
        Eur Respir J. 2009; 33: 1345-1353
        • Dickens J.A.
        • Lomas D.A.
        Why has it been so difficult to prove the efficacy of alpha-1-antitrypsin replacement therapy? Insights from the study of disease pathogenesis.
        Drug Des Devel Ther. 2011; 5: 391-405
        • Lange P.
        • Celli B.
        • Agustí A.
        • Boje Jensen G.
        • Divo M.
        • Faner R.
        • et al.
        Lung-function trajectories leading to chronic obstructive pulmonary disease.
        N Engl J Med. 2015; 373: 111-122
        • Chapman K.R.
        • Burdon J.G.
        • Piitulainen E.
        • Sandhaus R.A.
        • Seersholm N.
        • Stocks J.M.
        • et al.
        Intravenous augmentation treatment and lung density in severe α1-antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial.
        Lancet. 2015; 386: 360-368
        • Jedicke N.
        • Struever N.
        • Aggrawal N.
        • Welte T.
        • Manns M.P.
        • Malek N.P.
        • et al.
        α-1-antitrypsin inhibits acute liver failure in mice.
        Hepatology. 2014; 59: 2299-2308
        • Mueller C.
        • Flotte T.R.
        Gene-based therapy for alpha-1 antitrypsin deficiency.
        COPD. 2013; 10: 44-49
        • Massaro G.D.
        • Massaro D.
        Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats.
        Nat Med. 1997; 3: 675-677
        • Stolk J.
        • Stockley R.A.
        • Stoel B.C.
        • Cooper B.G.
        • Piitulainen E.
        • Seersholm N.
        • et al.
        Randomized controlled trial for emphysema with a selective agonist of the gamma type retinoic acid receptor.
        Eur Respir J. 2012; 40: 306-312
        • Donahue J.M.
        • Cassivi S.D.
        Lung volume reduction surgery for patients with alpha-1 antitrypsin deficiency emphysema.
        Thorac Surg Clin. 2009; 19: 201-208
        • Hillerdal G.
        • Mindus S.
        One- to four-year follow-up of endobronchial lung volume reduction in alpha-1-antitrypsin deficiency patients: a case series.
        Respiration. 2014; 88: 320-328
        • Devlin G.L.
        • Parfrey H.
        • Tew D.J.
        • Lomas D.A.
        • Bottomley S.P.
        Prevention of polymerization of M and Z α1-antitrypsin (α1-AT) with Trimethylamine N-Oxide. Implications for the treatment of α1-AT deficiency.
        Am J Respir Cell Mol Biol. 2001; 24: 727-732
        • Burrows J.A.J.
        • Willis L.K.
        • Perlmutter D.H.
        Chemical chaperones mediate increased secretion of mutant α1-antitrypsin (α1-AT) Z: a potential pharmacologcial strategy for prevention of liver injury and emphysema.
        Proc Natl Acad Sci U S A. 2000; 97: 1796-1801
        • Teckman J.H.
        Lack of effect of oral 4-phenylbutyrate on serum alpha-1-antitrypsin in patients with alpha-1-antitrypsin deficiency: a preliminary study.
        J Pediatr Gastroenterol Nutr. 2004; 39: 34-37
        • Hidvegi T.
        • Ewing M.
        • Hale P.
        • Dippold C.
        • Beckett C.
        • Kemp C.
        • et al.
        An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis.
        Science. 2010; 329: 229-232
        • Kaushal S.
        • Annamali M.
        • Blomenkamp K.
        • Rudnick D.
        • Halloran D.
        • Brunt E.M.
        • et al.
        Rapamycin reduces intrahepatic alpha-1-antitrypsin mutant Z protein polymers and liver injury in a mouse model.
        Exp Biol Med (Maywood). 2010; 235: 700-709
        • Nakagawa T.
        • Zhu H.
        • Morishima N.
        • Li E.
        • Xu J.
        • Yankner B.A.
        • et al.
        Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta.
        Nature. 2000; 403: 98-103
        • Pastore N.
        • Ballabio A.
        • Brunetti-Pierri N.
        Autophagy master regulator TFEB induces clearance of toxic SERPINA1/α-1-antitrypsin polymers.
        Autophagy. 2013; 9: 1094-1096
        • Bouchecareilh M.
        • Hutta D.M.
        • Szajnera P.
        • Flotte T.R.
        • Balch W.E.
        Histone Deacetylase inhibitor (HDACi) Suberoylanilide Hydroxamic Acid (SAHA) mediated correction of alpha-1 antitrypsin deficiency.
        J Biol Chem. 2012; 287: 38265-38278
        • Wooddell C.I.
        • Blomenkamp K.S.
        • Kanner S.
        • Chu Q.
        • Hamilton H.L.
        • Wakefield D.H.
        • et al.
        A hepatocyte-targeted RNAi-based treatment for liver disease associated with alpha-1-antitrypsin deficiency.
        in: Program and abstracts of the 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), November 7–11; 20142014 (Boston, Massachusetts)
        • Sehgal A.
        • Blomenkamp K.S.
        • Qian K.
        • Simon A.
        • Haslett P.
        • Barros S.
        • et al.
        Pre-clinical evaluation of ALN-AAT to ameliorate liver disease associated with alpha-1-antitrypsin deficiency.
        Gastroenterology. 2015; 148: S-975
        • Guo S.
        • Booten S.L.
        • Aghajan M.
        • Hung G.
        • Zhao C.
        • Blomenkamp K.
        • et al.
        Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin-related liver disease in mice.
        J Clin Invest. 2014; 124: 251-261
        • Lomas D.A.
        • Evans D.L.
        • Stone S.R.
        • Chang W.-S.W.
        • Carrell R.W.
        Effect of the Z mutation on the physical and inhibitory properties of α1-antitrypsin.
        Biochemistry. 1993; 32: 500-508
        • Skinner R.
        • Chang W.-S.W.
        • Jin L.
        • Pei X.
        • Huntington J.A.
        • Abrahams J.-P.
        • et al.
        Implications for function and therapy of a 2.9Å structure of binary-complexed antithrombin.
        J Mol Biol. 1998; 283: 9-14
        • Mahadeva R.
        • Dafforn T.R.
        • Carrell R.W.
        • Lomas D.A.
        Six-mer peptide selectively anneals to a pathogenic serpin conformation and blocks polymerisation: implications for the prevention of Z α1-antitrypsin related cirrhosis.
        J Biol Chem. 2002; 277: 6771-6774
        • Parfrey H.
        • Dafforn T.R.
        • Belorgey D.
        • Lomas D.A.
        • Mahadeva R.
        Inhibiting polymerisation: new therapeutic strategies for Z α1-antitrypsin related emphysema.
        Am J Respir Cell Mol Biol. 2004; 31: 133-139
        • Zhou A.
        • Stein P.E.
        • Huntington J.A.
        • Sivasothy P.
        • Lomas D.A.
        • Carrell R.W.
        How small peptides block and reverse serpin polymerization.
        J Mol Biol. 2004; 342: 931-941
        • Elliott P.R.
        • Pei X.Y.
        • Dafforn T.R.
        • Lomas D.A.
        Topography of a 2.0Å structure of α1-antitrypsin reveals targets for rational drug design to prevent conformational disease.
        Protein Sci. 2000; 9: 1274-1281
        • Parfrey H.
        • Mahadeva R.
        • Ravenhill N.A.
        • Zhou A.
        • Dafforn T.R.
        • Foreman R.C.
        • et al.
        Targeting a surface cavity of α1-antitrypsin to prevent conformational disease.
        J Biol Chem. 2003; 278: 33060-33066
        • Mallya M.
        • Phillips R.L.
        • Saldanha S.A.
        • Gooptu B.
        • Leigh Brown S.C.
        • Termine D.J.
        • et al.
        Small molecules block the polymerisation of Z α1-antitrypsin and increase the clearance of intracellular aggregates.
        J Med Chem. 2007; 50: 5357-5363
        • Tan L.
        • Perez J.
        • Mela M.
        • Miranda E.
        • Burling K.A.
        • Rouhani F.N.
        • et al.
        Characterising the association of latency with α1-antitrypsin polymerisation using a novel monoclonal antibody.
        Int J Biochem Cell Biol. 2015; 58: 81-91
        • Irving J.A.
        • Miranda E.
        • Haq I.
        • Perez J.
        • Kotov V.R.
        • Faull S.V.
        • et al.
        An antibody raised against a pathogenic serpin variant induces mutant-like behaviour in the wild-type protein.
        Biochem J. 2015; 468: 99-108
        • Ordóñez A.
        • Pérez J.
        • Tan L.
        • Dickens J.A.
        • Motamedi-Shad N.
        • Irving J.A.
        • et al.
        A single-chain variable fragment intrabody prevents intracellular polymerisation of Z α1-antitrypsin.
        FASEB J. 2015; 29: 2667-2678
        • Rashid S.T.
        • Corbineau S.
        • Hannan N.
        • Marciniak S.J.
        • Miranda E.
        • Alexander G.
        • et al.
        Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells.
        J Clin Invest. 2010; 120: 3127-3136
        • Wilson A.A.
        • Yin L.
        • Liesa M.
        • Segeritz C.P.
        • Mills J.A.
        • Shen S.S.
        • et al.
        Emergence of a stage-dependent human liver disease signature with directed differentiation of alpha-1 antitrypsin-deficient iPS cells.
        Stem Cell Rep. 2015; 4: 873-885
        • Yusa K.
        • Rashid S.T.
        • Strick-Marchand H.
        • Varela I.
        • Liu P.Q.
        • Paschon D.E.
        • et al.
        Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells.
        Nature. 2011; 478: 391-394
        • Patschull A.O.
        • Gooptu B.
        • Ashford P.
        • Daviter T.
        • Nobeli I.
        In silico assessment of potential druggable pockets on the surface of α1-antitrypsin conformers.
        PLoS One. 2012; 7e36612