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Therapeutics: Gene Therapy for Alpha-1 Antitrypsin Deficiency

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Alpha-1 Antitrypsin Deficiency

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1639))

Abstract

This review seeks to give an overview of alpha-1 antitrypsin deficiency, including the different disease phenotypes that it encompasses. We then describe the different therapeutic endeavors that have been undertaken to address these different phenotypes. Lastly we discuss future potential therapeutics, such as genome editing, and how they may play a role in treating alpha-1 antitrypsin deficiency.

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References

  1. Owen MC, Brennan SO, Lewis JH, Carrell RW (1983) Mutation of antitrypsin to antithrombin. N Engl J Med 309(12):694–698. doi:10.1056/NEJM198309223091203

    Article  CAS  PubMed  Google Scholar 

  2. Lockett AD, Van Demark M, Gu Y, Schweitzer KS, Sigua N, Kamocki K, Fijalkowska I, Garrison J, Fisher AJ, Serban K, Wise RA, Flotte TR, Mueller C, Presson RG Jr, Petrache HI, Tuder RM, Petrache I (2012) Effect of cigarette smoke exposure and structural modifications on the alpha-1 Antitrypsin interaction with caspases. Mol Med 18:445–454. doi:10.2119/molmed.2011.00207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Petrache I, Fijalkowska I, Medler TR, Skirball J, Cruz P, Zhen L, Petrache HI, Flotte TR, Tuder RM (2006) Alpha-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. Am J Pathol 169(4):1155–1166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rouhani F, Paone G, Smith NK, Krein P, Barnes P, Brantly ML (2000) Lung neutrophil burden correlates with increased pro-inflammatory cytokines and decreased lung function in individuals with alpha(1)-antitrypsin deficiency. Chest 117(5 Suppl 1):250s–251s

    Article  CAS  PubMed  Google Scholar 

  5. Jonigk D, Al-Omari M, Maegel L, Muller M, Izykowski N, Hong J, Hong K, Kim SH, Dorsch M, Mahadeva R, Laenger F, Kreipe H, Braun A, Shahaf G, Lewis EC, Welte T, Dinarello CA, Janciauskiene S (2013) Anti-inflammatory and immunomodulatory properties of alpha1-antitrypsin without inhibition of elastase. Proc Natl Acad Sci U S A 110(37):15007–15012. doi:10.1073/pnas.1309648110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Aggarwal Y (2006) Elastin fragments are pro-inflammatory in the progression of emphysema. Thorax 61(7):567–567. doi:10.1136/thx.2006.la0205

    Article  PubMed Central  Google Scholar 

  7. Marcus NY, Blomenkamp K, Ahmad M, Teckman JH (2012) Oxidative stress contributes to liver damage in a murine model of alpha-1-antitrypsin deficiency. Exp Biol Med (Maywood) 237(10):1163–1172. doi:10.1258/ebm.2012.012106

    Article  CAS  Google Scholar 

  8. Escribano A, Amor M, Pastor S, Castillo S, Sanz F, Codoner-Franch P, Dasi F (2015) Decreased glutathione and low catalase activity contribute to oxidative stress in children with alpha-1 antitrypsin deficiency. Thorax 70(1):82–83. doi:10.1136/thoraxjnl-2014-205898

    Article  PubMed  Google Scholar 

  9. Gadek JE, Klein HG, Holland PV, Crystal RG (1981) Replacement therapy of alpha 1-antitrypsin deficiency. Reversal of protease-antiprotease imbalance within the alveolar structures of PiZ subjects. J Clin Invest 68(5):1158–1165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hubbard RC, Fells G, Gadek J, Pacholok S, Humes J, Crystal RG (1991) Neutrophil accumulation in the lung in alpha 1-antitrypsin deficiency. Spontaneous release of leukotriene B4 by alveolar macrophages. J Clin Invest 88(3):891–897. doi:10.1172/jci115391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Baraldo S, Turato G, Lunardi F, Bazzan E, Schiavon M, Ferrarotti I, Molena B, Cazzuffi R, Damin M, Balestro E, Luisetti M, Rea F, Calabrese F, Cosio MG, Saetta M (2015) Immune activation in alpha1-antitrypsin-deficiency emphysema. Beyond the protease-antiprotease paradigm. Am J Respir Crit Care Med 191(4):402–409. doi:10.1164/rccm.201403-0529OC

    Article  CAS  PubMed  Google Scholar 

  12. O’Brien ME, Pennycooke K, Carroll TP, Shum J, Fee LT, O’Connor C, Logan PM, Reeves EP, McElvaney NG (2015) The impact of smoke exposure on the clinical phenotype of alpha-1 antitrypsin deficiency in Ireland: exploiting a national registry to understand a rare disease. COPD 12(Suppl 1):2–9. doi:10.3109/15412555.2015.1021913

    Article  PubMed  Google Scholar 

  13. Carp H, Miller F, Hoidal JR, Janoff A (1982) Potential mechanism of emphysema: alpha 1-proteinase inhibitor recovered from lungs of cigarette smokers contains oxidized methionine and has decreased elastase inhibitory capacity. Proc Natl Acad Sci U S A 79(6):2041–2045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Janus ED, Phillips NT, Carrell RW (1985) Smoking, lung function, and alpha 1-antitrypsin deficiency. Lancet (London, England) 1(8421):152–154

    Article  CAS  Google Scholar 

  15. Wewers MD, Casolaro MA, Sellers SE, Swayze SC, McPhaul KM, Wittes JT, Crystal RG (1987) Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. N Engl J Med 316(17):1055–1062. doi:10.1056/nejm198704233161704

    Article  CAS  PubMed  Google Scholar 

  16. Yoshimura K, Rosenfeld MA, Nakamura H, Scherer EM, Pavirani A, Lecocq JP, Crystal RG (1992) Expression of the human cystic fibrosis transmembrane conductance regulator gene in the mouse lung after in vivo intratracheal plasmid-mediated gene transfer. Nucleic Acids Res 20(12):3233–3240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Alino SF, Crespo J, Bobadilla M, Lejarreta M, Blaya C, Crespo A (1994) Expression of human alpha 1-antitrypsin in mouse after in vivo gene transfer to hepatocytes by small liposomes. Biochem Biophys Res Commun 204(3):1023–1030. doi:10.1006/bbrc.1994.2565

    Article  CAS  PubMed  Google Scholar 

  18. Alino SF, Bobadilla M, Crespo J, Lejarreta M (1996) Human alpha 1-antitrypsin gene transfer to in vivo mouse hepatocytes. Hum Gene Ther 7(4):531–536. doi:10.1089/hum.1996.7.4-531

    Article  CAS  PubMed  Google Scholar 

  19. Crepso J, Blaya C, Crespo A, Alino SF (1996) Long-term expression of the human alpha1-antitrypsin gene in mice employing anionic and cationic liposome vectors. Biochem Pharmacol 51(10):1309–1314

    Article  CAS  PubMed  Google Scholar 

  20. Alino SF (1997) Long-term expression of the human alpha1-antitrypsin gene in mice employing anionic and cationic liposome vector. Biochem Pharmacol 54(1):9–13

    Article  CAS  PubMed  Google Scholar 

  21. Canonico AE, Conary JT, Meyrick BO, Brigham KL (1994) Aerosol and intravenous transfection of human alpha 1-antitrypsin gene to lungs of rabbits. Am J Respir Cell Mol Biol 10(1):24–29. doi:10.1165/ajrcmb.10.1.8292378

    Article  CAS  PubMed  Google Scholar 

  22. Brigham KL, Lane KB, Meyrick B, Stecenko AA, Strack S, Cannon DR, Caudill M, Canonico AE (2000) Transfection of nasal mucosa with a normal alpha1-antitrypsin gene in alpha1-antitrypsin-deficient subjects: comparison with protein therapy. Hum Gene Ther 11(7):1023–1032. doi:10.1089/10430340050015338

    Article  CAS  PubMed  Google Scholar 

  23. Mastrangeli A, Danel C, Rosenfeld MA, Stratford-Perricaudet L, Perricaudet M, Pavirani A, Lecocq JP, Crystal RG (1993) Diversity of airway epithelial cell targets for in vivo recombinant adenovirus-mediated gene transfer. J Clin Invest 91(1):225–234. doi:10.1172/jci116175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Siegfried W, Rosenfeld M, Stier L, Stratford-Perricaudet L, Perricaudet M, Pavirani A, Lecocq JP, Crystal RG (1995) Polarity of secretion of alpha 1-antitrypsin by human respiratory epithelial cells after adenoviral transfer of a human alpha 1-antitrypsin cDNA. Am J Respir Cell Mol Biol 12(4):379–384. doi:10.1165/ajrcmb.12.4.7695917

    Article  CAS  PubMed  Google Scholar 

  25. Cerullo V, McCormack W, Seiler M, Mane V, Cela R, Clarke C, Rodgers JR, Lee B (2007) Antigen-specific tolerance of human alpha1-antitrypsin induced by helper-dependent adenovirus. Hum Gene Ther 18(12):1215–1224. doi:10.1089/hum.2006.036

    Article  CAS  PubMed  Google Scholar 

  26. Song S, Morgan M, Ellis T, Poirier A, Chesnut K, Wang J, Brantly M, Muzyczka N, Byrne BJ, Atkinson M, Flotte TR (1998) Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors. Proc Natl Acad Sci U S A 95(24):14384–14388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Song S, Embury J, Laipis PJ, Berns KI, Crawford JM, Flotte TR (2001) Stable therapeutic serum levels of human alpha-1 antitrypsin (AAT) after portal vein injection of recombinant adeno-associated virus (rAAV) vectors. Gene Ther 8(17):1299–1306. doi:10.1038/sj.gt.3301422

    Article  CAS  PubMed  Google Scholar 

  28. Song S, Scott-Jorgensen M, Wang J, Poirier A, Crawford J, Campbell-Thompson M, Flotte TR (2002) Intramuscular administration of recombinant adeno-associated virus 2 alpha-1 antitrypsin (rAAV-SERPINA1) vectors in a nonhuman primate model: safety and immunologic aspects. Mol Ther 6(3):329–335

    Article  CAS  PubMed  Google Scholar 

  29. Lu Y, Choi YK, Campbell-Thompson M, Li C, Tang Q, Crawford JM, Flotte TR, Song S (2006) Therapeutic level of functional human alpha 1 antitrypsin (hAAT) secreted from murine muscle transduced by adeno-associated virus (rAAV1) vector. J Gene Med 8(6):730–735. doi:10.1002/jgm.896

    Article  CAS  PubMed  Google Scholar 

  30. Liqun Wang R, McLaughlin T, Cossette T, Tang Q, Foust K, Campbell-Thompson M, Martino A, Cruz P, Loiler S, Mueller C, Flotte TR (2009) Recombinant AAV serotype and capsid mutant comparison for pulmonary gene transfer of alpha-1-antitrypsin using invasive and noninvasive delivery. Mol Ther 17(1):81–87. doi:10.1038/mt.2008.217

    Article  CAS  PubMed  Google Scholar 

  31. Conlon TJ, Cossette T, Erger K, Choi YK, Clarke T, Scott-Jorgensen M, Song S, Campbell-Thompson M, Crawford J, Flotte TR (2005) Efficient hepatic delivery and expression from a recombinant adeno-associated virus 8 pseudotyped alpha1-antitrypsin vector. Mol Ther 12(5):867–875. doi:10.1016/j.ymthe.2005.05.016

    Article  CAS  PubMed  Google Scholar 

  32. De BP, Heguy A, Hackett NR, Ferris B, Leopold PL, Lee J, Pierre L, Gao G, Wilson JM, Crystal RG (2006) High levels of persistent expression of alpha1-antitrypsin mediated by the nonhuman primate serotype rh.10 adeno-associated virus despite preexisting immunity to common human adeno-associated viruses. Mol Ther 13(1):67–76. doi:10.1016/j.ymthe.2005.09.003

    Article  CAS  PubMed  Google Scholar 

  33. Chiuchiolo MJ, Kaminsky SM, Sondhi D, Hackett NR, Rosenberg JB, Frenk EZ, Hwang Y, Van de Graaf BG, Hutt JA, Wang G, Benson J, Crystal RG (2013) Intrapleural administration of an AAVrh.10 vector coding for human alpha1-antitrypsin for the treatment of alpha1-antitrypsin deficiency. Hum Gene Ther Clin Dev 24(4):161–173. doi:10.1089/humc.2013.168

    Article  CAS  PubMed  Google Scholar 

  34. De B, Heguy A, Leopold PL, Wasif N, Korst RJ, Hackett NR, Crystal RG (2004) Intrapleural administration of a serotype 5 adeno-associated virus coding for alpha1-antitrypsin mediates persistent, high lung and serum levels of alpha1-antitrypsin. Mol Ther 10(6):1003–1010. doi:10.1016/j.ymthe.2004.08.022

    Article  CAS  PubMed  Google Scholar 

  35. Brantly ML, Spencer LT, Humphries M, Conlon TJ, Spencer CT, Poirier A, Garlington W, Baker D, Song S, Berns KI, Muzyczka N, Snyder RO, Byrne BJ, Flotte TR (2006) Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 alphal-antitrypsin (AAT) vector in AAT-deficient adults. Hum Gene Ther 17(12):1177–1186. doi:10.1089/hum.2006.17.1177

    Article  CAS  PubMed  Google Scholar 

  36. Brantly ML, Chulay JD, Wang L, Mueller C, Humphries M, Spencer LT, Rouhani F, Conlon TJ, Calcedo R, Betts MR, Spencer C, Byrne BJ, Wilson JM, Flotte TR (2009) Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proc Natl Acad Sci U S A 106(38):16363–16368. doi:10.1073/pnas.0904514106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Flotte TR, Conlon TJ, Poirier A, Campbell-Thompson M, Byrne BJ (2007) Preclinical characterization of a recombinant adeno-associated virus type 1-pseudotyped vector demonstrates dose-dependent injection site inflammation and dissemination of vector genomes to distant sites. Hum Gene Ther 18(3):245–256. doi:10.1089/hum.2006.113

    Article  CAS  PubMed  Google Scholar 

  38. Flotte TR, Trapnell BC, Humphries M, Carey B, Calcedo R, Rouhani F, Campbell-Thompson M, Yachnis AT, Sandhaus RA, McElvaney NG, Mueller C, Messina LM, Wilson JM, Brantly M, Knop DR, Ye GJ, Chulay JD (2011) Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing alpha1-antitrypsin: interim results. Hum Gene Ther 22(10):1239–1247. doi:10.1089/hum.2011.053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mueller C, Chulay JD, Trapnell BC, Humphries M, Carey B, Sandhaus RA, McElvaney NG, Messina L, Tang Q, Rouhani FN, Campbell-Thompson M, Fu AD, Yachnis A, Knop DR, Ye GJ, Brantly M, Calcedo R, Somanathan S, Richman LP, Vonderheide RH, Hulme MA, Brusko TM, Wilson JM, Flotte TR (2013) Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression. J Clin Invest 123(12):5310–5318. doi:10.1172/jci70314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zern MA, Ozaki I, Duan L, Pomerantz R, Liu SL, Strayer DS (1999) A novel SV40-based vector successfully transduces and expresses an alpha 1-antitrypsin ribozyme in a human hepatoma-derived cell line. Gene Ther 6(1):114–120. doi:10.1038/sj.gt.3300793

    Article  CAS  PubMed  Google Scholar 

  41. Cruz PE, Mueller C, Cossette TL, Golant A, Tang Q, Beattie SG, Brantly M, Campbell-Thompson M, Blomenkamp KS, Teckman JH, Flotte TR (2007) In vivo post-transcriptional gene silencing of alpha-1 antitrypsin by adeno-associated virus vectors expressing siRNA. Lab Investig 87(9):893–902. doi:10.1038/labinvest.3700629

    Article  CAS  PubMed  Google Scholar 

  42. Mueller C, Tang Q, Gruntman A, Blomenkamp K, Teckman J, Song L, Zamore PD, Flotte TR (2012) Sustained miRNA-mediated knockdown of mutant AAT with simultaneous augmentation of wild-type AAT has minimal effect on global liver miRNA profiles. Mol Ther 20(3):590–600. http://www.nature.com/mt/journal/v20/n3/suppinfo/mt2011292s1.html

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Horae Gene Therapy Center, University of Massachusetts Medical School, Suite 340, 55 Lake Avenue North, Worcester, MA, 01655, USA

    Alisha M. Gruntman & Terence R. Flotte

  2. Department of Pediatrics, University of Massachusetts Medical School, Suite 340, 55 Lake Avenue North, Worcester, MA, 01655, USA

    Terence R. Flotte

  3. Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Suite 340, 55 Lake Avenue North, Worcester, MA, 01655, USA

    Terence R. Flotte

Authors
  1. Alisha M. Gruntman
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  2. Terence R. Flotte
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Correspondence to Terence R. Flotte .

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Editors and Affiliations

  1. Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Florie Borel

  2. Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Christian Mueller

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Gruntman, A.M., Flotte, T.R. (2017). Therapeutics: Gene Therapy for Alpha-1 Antitrypsin Deficiency. In: Borel, F., Mueller, C. (eds) Alpha-1 Antitrypsin Deficiency . Methods in Molecular Biology, vol 1639. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7163-3_27

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  • DOI: https://doi.org/10.1007/978-1-4939-7163-3_27

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-7161-9

  • Online ISBN: 978-1-4939-7163-3

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