Advertisement

Muscle-Directed Gene Therapy for Alpha-1 Antitrypsin Deficiency

  • Alisha M. GruntmanEmail author
  • Terence R. Flotte
Chapter

Abstract

Alpha-1 antitrypsin (AAT) deficiency is a common monogenic disorder resulting in emphysema, which is currently treated with weekly infusions of protein replacement. We have reported achieving plasma wild-type (M) AAT concentrations at greater than 2% of the therapeutic level at 1 and 5 years after intramuscular (IM) administration of 6 × 1012 vg/kg of a recombinant adeno-associated virus serotype 1 (rAAV1)-AAT vector in AAT-deficient patients. This persistent expression was associated with a regulatory T cell (Treg) response to AAV1 capsid epitopes in the absence of any exogenous immune suppression. The patients also showed partial correction of functional biomarkers of AAT expression, including an increase in antineutrophil elastase capacity and a decrease in markers of neutrophil degranulation. Muscle-based gene therapy has allowed us to avoid targeting the liver, therefore preventing potential toxicity in patients where the hepatocytes are burdened with mutant AAT protein. Future muscle gene therapy will likely require dose escalation using a limb perfusion delivery method in order to obtain therapeutic serum levels of AAT while still avoiding delivery to the liver.

Keywords

Adeno-associated virus AAV Intramuscular Limb perfusion 

Notes

Acknowledgments

This work was supported in part by grants from the NIH (P01HL131471).

References

  1. 1.
    Carl-Bertil Laurell SE (1963) The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency. Scand J Clin Lab Invest 15(2):132–140.  https://doi.org/10.3109/15412555.2013.771956 CrossRefGoogle Scholar
  2. 2.
    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):1155–1166CrossRefGoogle Scholar
  3. 3.
    Petrache I, Fijalkowska I, Zhen L, Medler TR, Brown E, Cruz P, Choe KH, Taraseviciene-Stewart L, Scerbavicius R, Shapiro L, Zhang B, Song S, Hicklin D, Voelkel NF, Flotte T, Tuder RM (2006) A novel antiapoptotic role for alpha1-antitrypsin in the prevention of pulmonary emphysema. Am J Respir Crit Care Med 173(11):1222–1228.  https://doi.org/10.1164/rccm.200512-1842OC CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ganapathi MK, May LT, Schultz D, Brabenec A, Weinstein J, Sehgal PB, Kushner I (1988) Role of interleukin-6 in regulating synthesis of C-reactive protein and serum amyloid A in human hepatoma cell lines. Biochem Biophys Res Commun 157(1):271–277CrossRefGoogle Scholar
  5. 5.
    Mackiewicz A, Kushner I (1989) Interferon beta 2/B-cell stimulating factor 2/interleukin 6 affects glycosylation of acute phase proteins in human hepatoma cell lines. Scand J Immunol 29(3):265–271CrossRefGoogle Scholar
  6. 6.
    Heinrich PC, Castell JV, Andus T (1990) Interleukin-6 and the acute phase response. Biochem J 265(3):621–636CrossRefGoogle Scholar
  7. 7.
    Zaslow MC, Clark RA, Stone PJ, Calore JD, Snider GL, Franzblau C (1983) Human neutrophil elastase does not bind to alpha 1-protease inhibitor that has been exposed to activated human neutrophils. Am Rev Respir Dis 128(3):434–439CrossRefGoogle Scholar
  8. 8.
    George PM, Vissers MC, Travis J, Winterbourn CC, Carrell RW (1984) A genetically engineered mutant of alpha 1-antitrypsin protects connective tissue from neutrophil damage and may be useful in lung disease. Lancet 2(8417–8418):1426–1428CrossRefGoogle Scholar
  9. 9.
    Carroll TP, O’Connor CA, Floyd O, McPartlin J, Kelleher DP, O’Brien G, Dimitrov BD, Morris VB, Taggart CC, McElvaney NG (2011) The prevalence of alpha-1 antitrypsin deficiency in Ireland. Respir Res 12:91.  https://doi.org/10.1186/1465-9921-12-91 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Blanco I, de Serres FJ, Carcaba V, Lara B, Fernandez-Bustillo E (2012) Alpha-1 antitrypsin deficiency PI*Z and PI*S gene frequency distribution using on maps of the world by an inverse distance weighting (IDW) multivariate interpolation method. Hepat Mon 12(10 hcc):e7434.  https://doi.org/10.5812/hepatmon.7434 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    de Serres FJ, Blanco I, Fernandez-Bustillo E (2010) Ethnic differences in alpha-1 antitrypsin deficiency in the United States of America. Ther Adv Respir Dis 4(2):63–70.  https://doi.org/10.1177/1753465810365158 CrossRefPubMedGoogle Scholar
  12. 12.
    de Serres FJ, Luisetti M, Ferrarotti I, Blanco I, Fernandez-Bustillo E (2005) Alpha-1 antitrypsin deficiency in Italy: regional differences of the PIS and PIZ deficiency alleles. Monaldi Arch Chest Dis 63(3):133–141.  https://doi.org/10.4081/monaldi.2005.630 CrossRefPubMedGoogle Scholar
  13. 13.
    de Serres FJ, Blanco I, Fernandez-Bustillo E (2003) Genetic epidemiology of alpha-1 antitrypsin deficiency in southern Europe: France, Italy, Portugal and Spain. Clin Genet 63(6):490–509CrossRefGoogle Scholar
  14. 14.
    Huang X, Zheng Y, Zhang F, Wei Z, Wang Y, Carrell RW, Read RJ, Chen GQ, Zhou A (2016) Molecular mechanism of Z alpha1-antitrypsin deficiency. J Biol Chem 291(30):15674–15686.  https://doi.org/10.1074/jbc.M116.727826 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lomas DA, Evans DL, Finch JT, Carrell RW (1992) The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 357(6379):605–607.  https://doi.org/10.1038/357605a0 CrossRefPubMedGoogle Scholar
  16. 16.
    Stoller JK, Aboussouan LS (2012) A review of alpha1-antitrypsin deficiency. Am J Respir Crit Care Med 185(3):246–259.  https://doi.org/10.1164/rccm.201108-1428CI CrossRefPubMedGoogle Scholar
  17. 17.
    Crystal RG (1989) The alpha 1-antitrypsin gene and its deficiency states. Trends Genet 5(12):411–417CrossRefGoogle Scholar
  18. 18.
    Wewers MD, Casolaro MA, Sellers SE, Swayze SC, McPhaul KM, Wittes JT, Crystal RG (1987) Replacement therapy for Alpha1-antitrypsin deficiency associated with emphysema. N Engl J Med 316(17):1055–1062.  https://doi.org/10.1056/nejm198704233161704 CrossRefPubMedGoogle Scholar
  19. 19.
    Sharp HL, Bridges RA, Krivit W, Freier EF (1969) Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder. J Lab Clin Med 73(6):934–939PubMedGoogle Scholar
  20. 20.
    Sveger T (1988) The natural history of liver disease in alpha 1-antitrypsin deficient children. Acta Paediatr Scand 77(6):847–851CrossRefGoogle Scholar
  21. 21.
    Setoguchi Y, Jaffe HA, Chu CS, Crystal RG (1994) Intraperitoneal in vivo gene therapy to deliver alpha 1-antitrypsin to the systemic circulation. Am J Respir Cell Mol Biol 10(4):369–377.  https://doi.org/10.1165/ajrcmb.10.4.8136153 CrossRefPubMedGoogle Scholar
  22. 22.
    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.  https://doi.org/10.1016/j.ymthe.2004.08.022 CrossRefPubMedGoogle Scholar
  23. 23.
    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.  https://doi.org/10.1089/humc.2013.168 CrossRefPubMedGoogle Scholar
  24. 24.
    Chiuchiolo MJ, Kaminsky SM, Sondhi D, Mancenido D, Hollmann C, Crystal RG (2014) Phase I/II study of intrapleural administration of a serotype rh.10 replication-deficient adeno-associated virus gene transfer vector expressing the human alpha1-antitrypsin cDNA to individuals with alpha1-antitrypsin deficiency. Hum Gene Ther Clin Dev 25(3):112–133.  https://doi.org/10.1089/humc.2014.2513 CrossRefPubMedGoogle Scholar
  25. 25.
    Virella-Lowell I, Zusman B, Foust K, Loiler S, Conlon T, Song S, Chesnut KA, Ferkol T, Flotte TR (2005) Enhancing rAAV vector expression in the lung. J Gene Med 7(7):842–850.  https://doi.org/10.1002/jgm.759 CrossRefPubMedGoogle Scholar
  26. 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):14384–14388CrossRefGoogle Scholar
  27. 27.
    Mastrangeli A, O’Connell B, Aladib W, Fox PC, Baum BJ, Crystal RG (1994) Direct in vivo adenovirus-mediated gene transfer to salivary glands. Am J Phys 266(6 Pt 1):G1146–G1155Google Scholar
  28. 28.
    Kagami H, O’Connell BC, Baum BJ (1996) Evidence for the systemic delivery of a transgene product from salivary glands. Hum Gene Ther 7(17):2177–2184.  https://doi.org/10.1089/hum.1996.7.17-2177 CrossRefPubMedGoogle Scholar
  29. 29.
    Baum BJ, Berkman ME, Marmary Y, Goldsmith CM, Baccaglini L, Wang S, Wellner RB, Hoque AT, Atkinson JC, Yamagishi H, Kagami H, Parlow AF, Chao J (1999) Polarized secretion of transgene products from salivary glands in vivo. Hum Gene Ther 10(17):2789–2797.  https://doi.org/10.1089/10430349950016528 CrossRefPubMedGoogle Scholar
  30. 30.
    Perez P, Adriaansen J, Goldsmith CM, Zheng C, Baum BJ (2011) Transgenic alpha-1-antitrypsin secreted into the bloodstream from salivary glands is biologically active. Oral Dis 17(5):476–483.  https://doi.org/10.1111/j.1601-0825.2010.01775.x CrossRefPubMedGoogle Scholar
  31. 31.
    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.  https://doi.org/10.1038/mt.2011.292 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    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 Invest 87(9):893–902.  https://doi.org/10.1038/labinvest.3700629 CrossRefPubMedGoogle Scholar
  33. 33.
    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.  https://doi.org/10.1038/sj.gt.3301422 CrossRefPubMedGoogle Scholar
  34. 34.
    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.  https://doi.org/10.1016/j.ymthe.2005.05.016 CrossRefPubMedGoogle Scholar
  35. 35.
    Kessler PD, Podsakoff GM, Chen X, McQuiston SA, Colosi PC, Matelis LA, Kurtzman GJ, Byrne BJ (1996) Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein. Proc Natl Acad Sci U S A 93(24):14082–14087CrossRefGoogle Scholar
  36. 36.
    Xu L, Daly T, Gao C, Flotte TR, Song S, Byrne BJ, Sands MS, Parker Ponder K (2001) CMV-beta-actin promoter directs higher expression from an adeno-associated viral vector in the liver than the cytomegalovirus or elongation factor 1 alpha promoter and results in therapeutic levels of human factor X in mice. Hum Gene Ther 12(5):563–573.  https://doi.org/10.1089/104303401300042500 CrossRefPubMedGoogle Scholar
  37. 37.
    Song S, Laipis PJ, Berns KI, Flotte TR (2001) Effect of DNA-dependent protein kinase on the molecular fate of the rAAV2 genome in skeletal muscle. Proc Natl Acad Sci U S A 98(7):4084–4088.  https://doi.org/10.1073/pnas.061014598 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Song S, Lu Y, Choi YK, Han Y, Tang Q, Zhao G, Berns KI, Flotte TR (2004) DNA-dependent PK inhibits adeno-associated virus DNA integration. Proc Natl Acad Sci U S A 101(7):2112–2116.  https://doi.org/10.1073/pnas.0307833100 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    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.  https://doi.org/10.1089/hum.2006.17.1177 CrossRefPubMedGoogle Scholar
  40. 40.
    Amy Poirier MC-T, Tang Q, Scott-Jorgensen M, Combee L, Loiler S, Crawford J, Song S, Flotte TR (2004) Toxicology and biodistribution studies of a recombinant Adeno-associated virus 2-alpha-1 antitrypsin vector. Preclinica 2(1):43–51Google Scholar
  41. 41.
    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.  https://doi.org/10.1002/jgm.896 CrossRefPubMedGoogle Scholar
  42. 42.
    Chulay JD, Ye GJ, Thomas DL, Knop DR, Benson JM, Hutt JA, Wang G, Humphries M, Flotte TR (2011) Preclinical evaluation of a recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin made using a recombinant herpes simplex virus production method. Hum Gene Ther 22(2):155–165.  https://doi.org/10.1089/hum.2010.118 CrossRefPubMedGoogle Scholar
  43. 43.
    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.  https://doi.org/10.1073/pnas.0904514106 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    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.  https://doi.org/10.1089/hum.2011.053 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    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.  https://doi.org/10.1172/jci70314 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Mueller C, Gernoux G, Gruntman AM, Borel F, Reeves EP, Calcedo R, Rouhani FN, Yachnis A, Humphries M, Campbell-Thompson M, Messina L, Chulay JD, Trapnell B, Wilson JM, McElvaney NG, Flotte TR (2017) 5 year expression and neutrophil defect repair after gene therapy in Alpha-1 antitrypsin deficiency. Mol Ther.  https://doi.org/10.1016/j.ymthe.2017.03.029
  47. 47.
    Arruda VR, Schuettrumpf J, Herzog RW, Nichols TC, Robinson N, Lotfi Y et al (2004) Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1. Blood 103(1):85–92CrossRefGoogle Scholar
  48. 48.
    Rodino-Klapac LR, Janssen PM, Montgomery CL, Coley BD, Chicoine LG, Clark KR et al (2007) A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy. J Trans Med 5:45CrossRefGoogle Scholar
  49. 49.
    Rodino-Klapac LR, Montgomery CL, Bremer WG, Shontz KM, Malik V, Davis N et al (2010) Persistent expression of FLAG-tagged micro dystrophin in nonhuman primates following intramuscular and vascular delivery. Mol Ther 18(1):109–117CrossRefGoogle Scholar
  50. 50.
    Chicoine LG, Rodino-Klapac LR, Shao G, Xu R, Bremer WG, Camboni M et al (2014) Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin alpha2 surrogates. Mol Ther 22(4):713–724CrossRefGoogle Scholar
  51. 51.
    Chicoine LG, Montgomery CL, Bremer WG, Shontz KM, Griffin DA, Heller KN et al (2014) Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery. Mol Ther 22(2):338–347CrossRefGoogle Scholar
  52. 52.
    Su LT, Gopal K, Wang Z, Yin X, Nelson A, Kozyak BW et al (2005) Uniform scale-independent gene transfer to striated muscle after transvenular extravasation of vector. Circulation. 112(12):1780–1788CrossRefGoogle Scholar
  53. 53.
    Toromanoff A, Cherel Y, Guilbaud M, Penaud-Budloo M, Snyder RO, Haskins ME et al (2008) Safety and efficacy of regional intravenous (ri) versus intramuscular (im) delivery of rAAV1 and rAAV8 to nonhuman primate skeletal muscle. Mol Ther. 16(7):1291–1299CrossRefGoogle Scholar
  54. 54.
    Toromanoff A, Adjali O, Larcher T, Hill M, Guigand L, Chenuaud P et al (2010) Lack of immunotoxicity after regional intravenous (RI) delivery of rAAV to nonhuman primate skeletal muscle. Mol Ther 18(1):151–160CrossRefGoogle Scholar
  55. 55.
    Arruda VR, Stedman HH, Haurigot V, Buchlis G, Baila S, Favaro P et al (2010) Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B. Blood 115(23):4678–4688CrossRefGoogle Scholar
  56. 56.
    Le Guiner C, Montus M, Servais L, Cherel Y, Francois V, Thibaud JL et al (2014) Forelimb treatment in a large cohort of dystrophic dogs supports delivery of a recombinant AAV for exon skipping in Duchenne patients. Mol Ther 22(11):1923–1935CrossRefGoogle Scholar
  57. 57.
    Gruntman AM, Flotte TR (2015) Delivery of Adeno-associated virus gene therapy by intravascular limb infusion methods. Hum Gene Ther Clin Dev 26(3):159–164.  https://doi.org/10.1089/humc.2015.116 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pediatrics and Horae Gene Therapy CenterUniversity of Massachusetts Medical SchoolWorcesterUSA
  2. 2.Department of Clinical SciencesCummings School of Veterinary Medicine, Tufts UniversityNorth GraftonUSA

Personalised recommendations