Therapeutic targeting of misfolding and conformational change in α1-antitrypsin deficiency

Future Medicinal Chemistry

Volumn 6, Issue 9, 2014, Pages 1047-1065

  Nyon, Mun Peak ^a   Gooptu, Bibek ^a,b  

^a UNIVERSITY OF LONDON   (United Kingdom)

^b GUY S HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA 1 ANTITRYPSIN; POLYMER; MOLECULAR LIBRARY;

ALLELE; ALPHA ANTITRYPSIN DEFICIENCY; AMINO ACID SEQUENCE; CAENORHABDITIS ELEGANS; CONFORMATIONAL TRANSITION; ENDOPLASMIC RETICULUM; ENTROPY; ENZYME INHIBITION; GENE THERAPY; HUMAN; NONHUMAN; PATHOPHYSIOLOGY; PLURIPOTENT STEM CELL; POLYMERIZATION; PRIORITY JOURNAL; PROTEIN FOLDING; PROTEIN MALFOLDING; PROTEIN MISFOLDING; QUALITY CONTROL; REVIEW; TRANSGENIC MOUSE; TRANSGENIC PIZ MOUSE; WILD TYPE; ALPHA 1-ANTITRYPSIN DEFICIENCY; CHEMISTRY; DRUG EFFECTS; GENETICS; METABOLISM; MOLECULAR LIBRARY; PHARMACOLOGY; PROTEIN CONFORMATION;

ALPHA 1-ANTITRYPSIN; ALPHA 1-ANTITRYPSIN DEFICIENCY; HUMANS; PROTEIN CONFORMATION; PROTEIN FOLDING; SMALL MOLECULE LIBRARIES;

EID: 84905169292     PISSN: 17568919     EISSN: 17568927     Source Type: Journal    
DOI: 10.4155/fmc.14.58     Document Type: Review

References (149)

1. Laurell C-B, Eriksson S. The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency. Scand. J. Clin. Lab. Invest. 15, 132-140 (1963).
2. Silverman GA, Bird PI, Carrell RW et al. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, novel functions, mechanism of inhibition and a revised nomenclature. J. Biol. Chem. 276(36), 33293-33296 (2001).
3. Gooptu B, Dickens JA, Lomas DA. The molecular and cellular pathology of α1-antitrypsin deficiency. Trends Mol. Med. 20(2), 116-127 (2014).
4. Sharp HL, Bridges RA, Krivit W, Freier EF. Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognised inherited disorder. J. Lab. Clin. Med. 73(6), 934-939 (1969).
5. Eriksson S. Pulmonary emphysema and alpha1-antitrypsin deficiency. Acta Med. Scand. 175, 197-205 (1964).
6. De Serres FJ, Blanco I. Prevalence of α1-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review. Ther. Adv. Respir. Dis. 6, 277-295 (2012).
7. De Serres FJ, Blanco I, Fernández-Bustillo E. Genetic epidemiology of alpha-1-antitrypsin deficiency in southern Europe: France, Italy, Portugal and Spain. Clin. Genet. 63, 490-509 (2003).
8. Kim WJ, Wood AM, Barker AF et al. Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency. Respir. Res. 13, 16 (2012).
9. Demeo DL, Campbell EJ, Barker AF et al. IL10 polymorphisms are associated with airflow obstruction in severe alpha1-antitrypsin deficiency. Am. J. Resp. Crit. Care Med. 38, 114-120 (2008).
10. Pan S, Huang L, Mcpherson J et al. Single nucleotide polymorphism- mediated translational suppression of endoplasmic reticulum mannosidase I modifies the onset of end-stage liver disease in alpha1-antitrypsin deficiency. Hepatology 50, (2009).
11. Sveger T. Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N. Engl. J. Med. 294, 1316-1321 (1976).
12. Eriksson S, Carlson J, Velez R. Risk of cirrhosis and primary liver cancer in alpha1-antitrypsin deficiency. N. Engl. J. Med. 314, 736-739 (1986).
13. Sveger T. α1-antitrypsin deficiency in early childhood. Pediatrics 62, 22-25 (1978).
14. Teckman J, Perlmutter DH. Conceptual advances in the pathogenesis and treatment of childhood metabolic liver disease. Gastroenterology 108, 1263-1279 (1995).
15. Lomas DA, Evans DL, Finch JT, Carrell RW. The mechanism of Z alpha1-antitrypsin accumulation in the liver. Nature 357, 605-607 (1992).
16. Baugh RJ, Travis J. Human leukocyte granule elastase: rapid isolation and characterization. Biochemistry 15(4), 836-841 (1976).
17. Hartl D, Latzin P, Hordijk P et al. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat. Med. 13, 1423-1430 (2007).
18. Sandhaus RA, Turino G. Neutrophil elastase-mediated lung disease. COPD 10(Suppl. 1), 60-63 (2013).
19. Fregonese L, Stolk J, Frants RR, Veldhuisen B. Alpha-1 antitrypsin null mutations and severity of emphysema. Respir. Med. 102, 876-884 (2008).
20. Elliott PR, Bilton D, Lomas DA. Lung polymers in Z α1-antitrypsin related emphysema. Am. J. Respir. Cell. Mol. Biol. 18(5), 670-674 (1998).
21. Mahadeva R, Atkinson C, Li J et al. Polymers of Z α1-antitrypsin co-localise with neutrophils in emphysematous alveoli and are chemotactic in vivo. Am. J. Pathol. 166(2), 377-386 (2005).
22. Parmar JS, Mahadeva R, Reed BJ 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 26, 723-730 (2002).
23. Gooptu B, Ekeowa UI, Lomas DA. Mechanisms of emphysema in α1-antitrypsin deficiency: molecular and cellular insights. Eur. Respir. J. 34(2), 475-488 (2009).
24. Hunt LT, Dayhoff MO. A surprising new protein superfamily containing ovalbumin, antithrombin III, and alpha1-proteinase inhibitor. Biochem. Biophys. Res. Commun. 95(2), 864-871 (1980).
25. Huber R, Carrell RW. Implications of the three-dimensional structure of α1-antitrypsin for structure and function of serpins. Biochemistry 28(23), 8951-8966 (1989).
26. Gooptu B, Lomas DA. Conformational pathology of the serpins: themes, variations and therapeutic strategies. Annu. Rev. Biochem. 78, 147-176 (2009).
27. Davis RL, Shrimpton AE, Holohan PD et al. Familial dementia caused by polymerisation of mutant neuroserpin. Nature 401, 376-379 (1999).
28. Davis RL, Shrimpton AE, Carrell RW et al. Association between conformational mutations in neuroserpin and onset and severity of dementia. Lancet 359, 2242-2247 (2002).
29. Yepes M, Lawrence DA. Tissue-type plasminogen activator and neuroserpin: a well-balanced act in the nervous system? Trends Cardiovasc. Med. 14, 173-180 (2004).
30. Gooptu B, Lomas DA. Polymers and inflammation: disease mechanisms of the serpinopathies. J. Exp. Med. 205(7), 1529-1534 (2008).
31. Miranda E, Perez J, Ekeowa UI et al. A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with α1-antitrypsin deficiency. Hepatology 52, 1078-1088 (2010).
32. Ekeowa UI, Freeke J, Miranda E et al. Defining the mechanism of polymerization in the serpinopathies. Proc. Natl Acad. Sci. USA 107, 17146-17151 (2010).
33. Nyon MP, Segu L, Cabrita LD et al. Structural dynamics associated with intermediate formation in an archetypal conformational disease. Structure 20(3), 504-512 (2012).
34. Huntington JA, Read RJ, Carrell RW. Structure of a serpin-protease complex shows inhibition by deformation. Nature 407, 923-926 (2000).
35. Johnson DJ, Li W, Adams TE, Huntington JA. Antithrombin-S195A factor Xa-heparin structure reveals the allosteric mechanism of antithrombin activation. EMBO J. 25(9), 2029-2037 (2006).
36. Elliott PR, Abrahams J-P, Lomas DA. Wildtype α1-antitrypsin is in the canonical inhibitory conformation. J. Mol. Biol. 275(3), 419-425 (1998).
37. Chang Y-P, Mahadeva R, Patschull AOM et al. Targeting serpins in high-throughput and structure-based drug design. Methods Enzymol. 501, 139-175 (2011).
38. Carrell RW, Gooptu B. Conformational changes and disease-serpins, prions and Alzheimer's. Curr. Opin. Struct. Biol. 8, 799-809 (1998).
39. Bucciantini M, Giannoni E, Chiti F et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416, 507-511 (2002).
40. Balch WE, Sznajder JI, Budinger S et al. Malfolded protein structure and proteostasis in lung diseases. Am. J. Respir. Crit. Care Med. 189(1), 96-103 (2014).
41. Whisstock JC, Bottomley SP. Molecular gymnastics: serpin structure, folding and misfolding. Curr. Opin. Struct. Biol. 16, 761-768 (2006).
42. Loebermann H, Tokuoka R, Deisenhofer J, Huber R. Human α1-proteinase inhibitor. Crystal structure analysis of two crystal modifications, molecular model and preliminary analysis of the implications for function. J. Mol. Biol. 177, 531-556 (1984).
43. Pemberton PA, Stein PE, Pepys MB, Potter JM, Carrell RW. Hormone binding globulins undergo serpin conformational change in inflammation. Nature 336, 257-258 (1988).
44. Chan WL, Carrell RW, Zhou A, Read RJ. How changes in affinity of corticosteroid-binding globulin modulate free cortisol concentration. J. Clin. Endocrinol. Metab. 98(8), 3315-3322 (2013).
45. Stein PE, Carrell RW. What do dysfunctional serpins tell us about molecular mobility and disease? Nat. Struct. Biol. 2(2), 96-113 (1995).
46. Dafforn TR, Mahadeva R, Elliott PR, Sivasothy P, Lomas DA. A kinetic mechanism for the polymerisation of α1-antitrypsin. J. Biol. Chem. 274, 9548-9555 (1999).
47. Gooptu B, Hazes B, Chang W-SW 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. USA 97(1), 67-72 (2000).
48. Yamasaki M, Sendall TJ, Pearce MC, Whisstock JC, Huntington JA. Molecular basis of alpha1-antitrypsin deficiency revealed by the structure of a domain-swapped trimer. EMBO Rep. 12(10), 1011-1017 (2011).
49. Yamasaki M, Li W, Johnson DJ, Huntington JA. Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization. Nature 455, 1255-1258 (2008).
50. Patschull AOM, Segu L, Nyon MP et al. Therapeutic target site variability in α1-antitrypsin characterized at high resolution. Acta Cryst. F 67, 1492-1497 (2011).
51. Elliott PR, Pei XY, Dafforn TR, Lomas DA. Topography of a 2.0Å structure of α1-antitrypsin reveals targets for rational drug design to prevent conformational disease. Protein Sci. 9, 1274-1281 (2000).
52. Pearce MC, Morton CJ, Feil SC et al. Preventing serpin aggregation: the molecular mechanism of citrate action upon antitrypsin unfolding. Protein Sci. 17(12), 2127-2133 (2008).
53. Schechter I, Berger A. On the size of the active site in proteases. 1. Papain. Biochem. Biophys. Res. Commun. 27(2), 157-162 (1967).
54. Seo EJ, Im H, Maeng J-S, Kim KE, Yu M-H. Distribution of the native strain in human α1-antitrypsin and its association with protease inhibitor function. J. Biol. Chem. 275(22), 16904-16909 (2000).
55. Ryu S-E, Choi H-J, Kwon K-S, Lee KN, Yu M-H. The native strains in the hydrophobic core and flexible reactive loop of a serine protease inhibitor: crystal structure of an uncleaved α1-antitrypsin at 2.7Å. Structure 4, 1181-1192 (1996).
56. Lee KN, Park SD, Yu M-H. Probing the native strain in α1-antitrypsin. Nat. Struc. Biol. 3(6), 497-500 (1996).
57. Lee C, Park S-H, Lee M-Y, Yu M-H. Regulation of protein function by native metastability. Proc. Natl Acad. Sci. USA 97(14), 7727-7731 (2000).
58. Parfrey H, Mahadeva R, Ravenhill N et al. Targeting a surface cavity of α1-antitrypsin to prevent conformational disease. J. Biol. Chem. 278(35), 33060-33066 (2003).
59. Knaupp AS, Levina V, Robertson AL, Pearce MC, Bottomley SP. Kinetic instability of the serpin Z α1-antitrypsin promotes aggregation. J. Mol. Biol. 396, 375-383 (2010).
60. Ekeowa UI, Freeke J, Miranda E et al. Defining the mechanism of polymerization in the serpinopathies. Proc. Natl Acad. Sci. USA 107, 17146-17151 (2010).
61. Tew DJ, Bottomley SP. Probing the equilibrium denaturation of the serpin α1-antitrypsin with single tryptophan mutants; evidence for structure in the urea unfolded state. J. Mol. Biol. 313, 1161-1169 (2001).
62. James EL, Whisstock JC, Gore MG, Bottomley SP. Probing the unfolding pathway of α1-antitrypsin. J. Biol. Chem. 274, 9482-9488 (1999).
63. Koloczek H, Guz A, Kaszycki P. Fluorescence-detected polymerisation of human α1-antitrypsin. J. Prot. Chem. 15(5), 447-454 (1996).
64. Tsutsui Y, Cruz RD, Wintrode PL. Folding mechanism of the metastable serpin α1-antitrypsin. Proc. Natl Acad. Sci. USA 109(12), 4467-4472 (2012).
65. Tsutsui Y, Kuri B, Sengupta T, Wintrode PL. The structural basis of serpin polymerization studied by hydrogen/deuterium exchange and mass spectrometry. J. Biol. Chem. 283, 30804-30811 (2008).
66. Irving JA, Ekeowa UI, Belorgey D et al. The serpinopathies: studying serpin polymerization in vivo. Methods Enzymol. 501, 421-466 (2011).
67. Huntington JA, Pannu NS, Hazes B, Read R, Lomas DA, Carrell RW. A 2.6Å structure of a serpin polymer and implications for conformational disease. J. Mol. Biol. 293, 449-455 (1999).
68. Haq I, Irving JA, Faull SV et al. Reactive centre loop mutants of α-1-antitrypsin reveal position-specific effects on intermediate formation along the polymerization pathway. Biosci. Rep. 33, 499-511 (2013).
69. Le A, Steiner JL, Ferrell GA, Shaker JC, Sifers RN. Association between calnexin and a secretion-incompetent variant of human α1-antitrypsin. J. Biol. Chem. 269(10), 7514-7519 (1994).
70. Wu Y, Swulius MT, Moremen KW, Sifers RN. Elucidation of the molecular logic by which misfolded α1-antitrypsin is preferentially selected for degradation. Proc. Natl Acad. Sci. USA 100(14), 8229-8234 (2003).
71. Sifers RN, Brashears-Macatee S, Kidd VJ, Muensch H, Woo SLC. A frameshift mutation results in a truncated α1-antitrypsin that is retained within the rough endoplasmic reticulum. J. Biol. Chem. 263(15), 7330-7335 (1988).
72. Teckman JH, Burrows J, Hidvegi T, Schmidt B, Hale PD, Perlmutter DH. The proteasome participates in degradation of mutant α1-antitrypsin Z in the endoplasmic reticulum of hepatoma-derived hepatocytes. J. Biol. Chem. 276, 44865-44872 (2001).
73. Sifers RN. Intracellular processing of alpha1-antitrypsin. Proc. Am. Thorac. Soc. 7, 376-380 (2010).
74. Wang T, Hebert DN. ER degradation-enhancing α-mannosidase-like protein. Nat. Struct. Biol. 10(5), 319-321 (2003).
75. Schafer A, Wolf DH. Sec61p is part of the endoplasmic reticulum-associated degradation machinery. EMBO J. 28, 2874-2884 (2009).
76. Greenblatt EJ, Olzmann JA, Kopito RR. Derlin-1 is a rhomboid pseudoprotease required for the dislocation of mutant α-1 antitrypsin from the endoplasmic reticulum. Nat. Struct. Mol. Biol. 18(10), 1147-1152 (2011).
77. Iida Y, Fujimori T, Okawa K, Nagata K, Wada I, Hosokawa N. SEL1L protein critically determines the stability of the HRD1-SEL1L endoplasmic reticulum-associated degradation (ERAD) complex to optimize the degradation kinetics of ERAD substrates. J. Biol. Chem. 286(19), 16929-16939 (2010).
78. Hosokawa N, You Z, Tremblay LO, Nagata K, Herscovics A. Stimulation of ERAD of misfolded null Hong Kong α1-antitrypsin by Golgi α1,2-mannosidases. Biochem. Biophys. Res. Commun. 362, 626-632 (2007).
79. Marciniak SJ, Ron D. Endoplasmic reticulum stress signaling in disease. Physiol. Rev. 86(4), 1133-1149 (2006).
80. Davies MJ, Lomas DA. The molecular aetiology of the serpinopathies. Int. J. Biochem. Cell. Biol. 40(6-7), 1273-1286 (2008).
81. Ordóñez A, Snapp EL, Tan L, Miranda E, Marciniak SJ, Lomas DA. Endoplasmic reticulum polymers impair luminal protein mobility and sensitise to cellular stress in α1-antitrypsin deficiency. Hepatology 57, 2049-2060 (2013).
82. Hidvegi T, Schmidt BZ, Hale P, Perlmutter DH. Accumulation of mutant a1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and-12, NFkB, and BAP31 but not the unfolded protein response. J. Biol. Chem. 280, 39002-39015 (2005).
83. Teckman JH, Perlmutter DH. Retention of mutant α1-antitrypsin Z in endoplasmic reticulum is associated with an autophagic response. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G961-G974 (2000).
84. Kamimoto T, Shoji S, Hidvegi T et al. Intracellular inclusions containing mutant alpha1-antitrypsin Z are propagated in the absence of autophagic activity. J. Biol. Chem. 281(7), 4467-4476 (2006).
85. Kroeger H, Miranda E, Macleod I et al. Endoplasmic reticulum-associated degradation (ERAD) and autophagy cooperate to degrade polymerogenic mutant serpins. J. Biol. Chem. 284, 22793-22802 (2009).
86. Davies MJ, Miranda E, Roussel BD, Kaufman RJ, Marciniak SJ, Lomas DA. Neuroserpin polymers activate NF-kappaB by a calcium signaling pathway that is independent of the unfolded protein response. J. Biol. Chem. 284(27), 18202-18209 (2009).
87. Pahl HL, Baeuerle PA. The ER-overload response: activation of NF-kappa B. Trends Biochem. Sci 22, 63-67 (1997).
88. Carroll TP, Greene CM, O'connor CA, Nolan AM, O'neill SJ, Mcelvaney NG. Evidence for unfolded protein response activation in monocytes from individuals with alpha-1 antitrypsin deficiency. J. Immunol. 184(8), 4538-4546 (2010).
89. Bouchecareilh M, Hutt DM, Szaner P, Flotte TR, Balch WE. Histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA)-mediated correction of α1-antitrypsin deficiency. J. Biol. Chem. 287, 38265-38278 (2012).
90. Mallya M, Phillips RL, Saldanha SA, Gooptu B, Leigh Brown SC, Termine DJ, Shirvani AM, Wu Y, Sifers RN, Abagyan R, Lomas DA. Small molecules block the polymerization of Z alpha1-antitrypsin and increase the clearance of intracellular aggregates. J. Med. Chem. 50(22), 5357-5363 (2007).
91. Rashid ST, Corbineau S, Hannan N et al. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J. Clin. Invest. 120, 3127-3136 (2010).
92. Somers A, Jean JC, Sommer CA et al. Generation of transgene-free lung disease-specific human induced pluripotent stem cells using a single excisable lentiviral stem cell cassette. Stem Cells 28(10), 1728-1740 (2010).
93. Yusa K, Rashid ST, Strick-Marchand H et al. Targeted gene correction of alpha1-antitrypsin deficiency in induced pluripotent stem cells. Nature 478(7369),391-394 (2011).
94. Schipanski A, Lange S, Segref A et al. A novel interaction between ageing and ER overload in a protein conformational dementia. Genetics 193(3), 865-876 (2013).
95. Gidalevitz T, Wang N, Deravaj T, Alexander-Floyd J, Morimoto RI. Natural genetic variation determines susceptibility to aggregation or toxicity in a C. elegans model for polyglutamine disease. BMC Biol. 11(1), 100 (2013).
96. Mccoll G, Roberts BR, Pukala TL et al. Utility of an improved model of amyloid-beta (Aβ1-42) toxicity in Caenorhabditis elegans for drug screening for Alzheimer's disease. Mol. Neurodegener. 7, 57 (2012).
97. Gosai SJ, Kwak JH, Luke CJ et al. Automated high-content live animal drug screening using C. elegans expressing the aggregation prone serpin α1-antitrypsin Z. PLoS ONE 5(11), e15460 (2010).
98. Silverman GA, Luke CJ, Bhatia SR et al. Modeling molecular and cellular aspects of human disease using the nematode Caenorhabditis elegans. Pediatr. Res. 65(1), 10-18 (2009).
99. Hamamichi S, Rivas RN, Knight AL, Cao S, Caldwell KA, Caldwell GA. Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson's disease model. Proc. Natl Acad. Sci. USA 105(2), 728-733 (2007).
100. Carlson J, Rogers B, Sifers R et al. Accumulation of PiZ alpha 1-antitrypsin causes liver damage in transgenic mice. J. Clin. Invest. 83(4), 1183-1190 (1989).
101. Ali R, Perfumo S, Rocca CD et al. Evaluation of a transgenic mouse model for alpha-1-antitrypsin (AAT) related liver disease. Ann. Hum. Genet. 58, 305-320 (1994).
102. Hidvegi T, Ewing M, Hale P et al. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 329, 229-232 (2010).
103. Burrows JaJ, Willis LK, Perlmutter DH. Chemical chaperones mediate increased secretion of mutant α1-antitrypsin. Proc. Natl Acad. Sci. USA 97(4), 1796-1801 (2000).
104. Kaushal S, Annamali M, Blomenkamp K et al. Rapamycin reduces intrahepatic alpha-1-antitrypsin mutant Z protein polymers and liver injury in a mouse model. Exp. Biol. Med. 235(6), 700-709 (2010).
105. Alam S, Li Z, Janciauskiene S, Mahadeva R. Oxidation of Z alpha1-antitrypsin by cigarette smoke induces polymerization: a novel mechanism of early-onset emphysema. Am. J. Respir. Cell Mol. Biol. 45(2), 261-269 (2011).
106. Li C, Xiao P, Gray SJ, Weinberg MS, Samulski RJ. Combination therapy utilizing shRNA knockdown and an optimized resistant transgene for rescue of diseases caused by misfolded proteins. Proc. Natl. Acad. Sci. USA 108(34), 14258-14263 (2011).
107. Marcus NY, Blomenkamp K, Ahmad M, Teckman JH. Oxidative stress contributes to liver damage in a murine model of alpha-1-antitrypsin deficiency. Exp. Biol. Med. 237(10), 1163-1172 (2012).
108. Janus ED, Phillips NT, Carrell RW. Smoking, lung function, and α1-antitrypsin deficiency. Lancet 152-154 (1985).
109. Kemmer N, Kaiser T, Zacharias V, Neff GW. Alpha-1-antitrypsin deficiency: outcomes after liver transplantation. Transplant. Proc. 40(5), 1492-1494 (2008).
110. Hughes MG, Jr., Khan KM, Gruessner AC et al. Long-term outcome in 42 pediatric liver transplant patients with alpha 1-antitrypsin deficiency: a single-center experience. Clin. Transplant. 25(5), 731-736 (2011).
111. Burton CM, Milman N, Carlsen J et al. The Copenhagen National Lung Transplant Group: survival after single lung, double lung, and heart-lung transplantation. J. Heart Lung Transplant. 24(11), 1834-1843 (2005).
112. Tanash HA, Riise GC, Hansson L, Nilsson PM, Piitulainen E. Survival benefit of lung transplantation in individuals with severe alpha1-anti-trypsin deficiency (PiZZ) and emphysema. J. Heart Lung Transplant. 30(12), 1342-1347 (2011).
113. Wewers MD, Casolaro MA, Sellers SE et al. Replacement therapy for alpha1-antitrypsin deficiency associated with emphysema. N. Engl. J. Med. 316, 1055-1062 (1987).
114. Gross B, Grebe M, Wencker M, Stoller JK, Bjursten LM, Janciauskiene S. New Findings in PiZZ alpha1-antitrypsin deficiency-related panniculitis. Demonstration of skin polymers and high dosing requirements of intravenous augmentation therapy. Dermatology 218(4), 370-375 (2009).
115. O'riordan K, Blei A, Rao MS, Abecassis M. α1-antitrypsin deficiency-associated panniculitis. Resolution with intravenous α1-antitrypsin administration and liver transplantation. Transplantation 63(3), 480-482 (1997).
116. Hubbard RC, Sellers RE, Caerski DB, Stephens L, Crystal RG. Biochemical efficacy and safety of monthly augmentation therapy for α-1antitrypsin deficiency. JAMA 260, 651-652 (1988).
117. Stockley RA, Bayley DL, Unsal U, Dowson LJ. The effect of augmentation therapy on bronchial inflammation in α1-antitrypsin deficiency. Am. J. Resp. Crit. Care Med. 165, 1494-1498 (2002).
118. Dirksen A, Piitulainen E, Parr DG et al. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency. Eur. Respir. J. 33, 1345-1353 (2009).
119. GØtzsche PC, Johansen HK. Intravenous alpha-1 antitrypsin augmentation therapy: systematic review. Dan. Med. Bull. 57, A4175 (2010).
120. Stockley RA, Miravitlles M, Vogelmeier C. Augmentation therapy for alpha-1 antitrypsin deficiency: towards a personalised approach. Orphanet. J. Rare Dis. 8, 149 (2013).
121. The Alpha-1-Antitrypsin Deficiency Registry Study Group: Survival and FEV1 decline in individuals with severe deficiency of a1-antitrypsin. Am. J. Respir. Crit. Care Med. 158, 49-59 (1998).
122. Chapman KR, Burdon JG, Piitulainen E et al. IV alpha1 antitrypsin (A1AT) preserves lung density in homozygous alpha1 antitrypsin deficiency (A1ATD); a randomized, placebo-controlled trial. Am. J. Resp. Crit. Care Med. 187, Abstract 45385 (2013).
123. Tonelli AR, Brantly ML. Augmentation therapy in alpha-1 antitrypsin deficiency: advances and controversies. Ther. Adv. Respir. Dis. 4(5), 289-312 (2010).
124. Mcnab GL, Ahmad A, Mistry D, Stockley RA. Modification of gene expression and increase in a1-antitrypsin (a1-AT) secretion after homologous recombination in a1-AT-deficient monocytes. Hum. Gene Ther. 18, 1171-1177 (2007).
125. Alnylam Pharmaceuticals: developing an RNAi therapeutic for liver disease associated with alpha-1-antitrypsin deficiency. www.alnylam.com/capella/wp- content/uploads/2012/11/ALNY-AASLD-AAT-Nov20121.pdf
126. Guo S, Booten SL, Aghajan M et al. Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin-related liver disease in mice. J. Clin. Invest. 124(1), 251-261 (2014)
127. Bouchecareilh M, Conkright JJ, Balch WE. Proteostasis strategies for restoring alpha1-antitrypsin deficiency. Proc. Am. Thorac Soc. 7(6), 415-422 (2010).
128. Perlmutter DH. Chemical chaperones: A pharmacological strategy for disorders of protein folding and trafficking. Pediatr. Res. 52(6), 832-836 (2002).
129. Sharp LK, Mallya M, Kinghorn KJ et al. Sugar and alcohol molecules provide a therapeutic strategy for the serpinopathies that cause dementia and cirrhosis. FEBS J. 273(11), 2540-2552 (2006).
130. Devlin GL, Parfrey H, Tew DJ, Lomas DA, Bottomley SP. 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. 24(6), 727-732 (2001).
131. Burrows JJ, Willis LK, Perlmutter DH. 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. USA 97, 1796-1801 (2000).
132. Teckman JH. Lack of effect of oral 4-phenylbutyrate on serum alpha-1-antitrypsin in patients with a-1-antitrypsin deficiency: a preliminary study. J. Pediatr. Gastroenterol. Nutr 39(1), 34-37 (2004).
133. Chang YP, Mahadeva R, Chang WS, Lin SC, Chu YH. Small-molecule peptides inhibit Z alpha1-antitrypsin polymerization. J. Cell Mol. Med. 13, 2304-2236 (2009).
134. Chang YP, Mahadeva R, Chang WSW, Shukla A, Dafforn TR, Chu YH. Identification of a 4-mer peptide inhibitor that effectively blocks the polymerization of pathogenic Z α1-antitrypsin. Am. J. Respir. Cell Mol. Biol. 35(5), 540-548 (2006).
135. Parfrey H, Dafforn TR, Belorgey D, Lomas DA, Mahadeva R. Inhibiting polymerisation: new therapeutic strategies for Z α1-antitrypsin related emphysema. Am. J. Respir. Cell Mol. Biol. 31, 133-139 (2004).
136. Mahadeva R, Dafforn TR, Carrell RW, Lomas DA. 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. 277(9), 6771-6774 (2002).
137. Patschull AOM, Gooptu B, Ashford P, Daviter T, Nobeli I. In silico assessment of potential druggable pockets on the surface of α1-antitrypsin conformers. PLoS ONE 7(5), e36612 (2012).
138. Gooptu B, Miranda E, Nobeli I et al. Crystallographic and cellular characterisation of two mechanisms stablising the native fold of α1-antitrypsin : implications for disease and drug design. J. Mol. Biol. 387, 857-868 (2009).
139. Fitton HL, Pike RN, Carrell RW, Chang W-SW. Mechanisms of antithrombin polymerisation and heparin activation probed by insertion of synthetic reactive loop peptides. Biol. Chem. 378, 1059-1063 (1997).
140. Skinner R, Chang W-SW, Jin L et al. Implications for function and therapy of a 2.9Å structure of binary-complexed antithrombin. J. Mol. Biol. 283(1), 9-14 (1998).
141. Alam S, Wang J, Janciauskiene S, Mahadeva R. Preventing and reversing the cellular consequences of Z alpha-1 antitrypsin accumulation by targeting s4A. J. Hepatol. 57(1), 116-124 (2012).
142. Mcnab GL, Dafforn TR, Wood A, Sapey E, Stockley RA. A novel model and molecular therapy for Z alpha-1 antitrypsin deficiency. Mamm Genome 23(3-4), 241-249 (2012).
143. New collaboration to develop treatments for liver disease. www.cam.ac.uk/research/news/new-collaboration-to-develop-treatments-for-liver- disease
144. Lomas DA, Elliott PR, Carrell RW. Commercial plasma α1-antitrypsin contains a conformationally inactive, latent component. Eur. Respir. J. 10, 672-675 (1997).
145. Kroeger H, Miranda E, Macleod I et al. Endoplasmic reticulum-associated degradation (ERAD) and autophagy cooperate to degrade polymerogenic mutant serpins. J. Biol. Chem. 284(34), 22793-22802 (2009).
146. Pastore N, Blomenkamp K, Annunziata F et al. Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and correction of hepatic disease in alpha-1-anti-trypsin deficiency. EMBO Mol. Med. 5(3), 397-412 (2013).
147. Mueller C, Flotte TR. Gene-based therapy for alpha-1 antitrypsin deficiency. COPD 10(Suppl 1), 44-49 (2013).
148. Van Goor F, Hadida S, Grootenhuis PD et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc. Natl Acad Sci. USA 108(46), 18843-18848 (2011).
149. Van Goor F, Hadida S, Grootenhuis PD et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc. Natl Acad Sci. USA 106(44), 18825-18830 (2009).