Skip to main content
SpringerLink
Log in

Helper-Dependent Adenoviral Vectors for Gene Therapy of Inherited Diseases

  • Chapter
  • First Online:
Safety and Efficacy of Gene-Based Therapeutics for Inherited Disorders

  • 850 Accesses

Abstract

Helper-dependent adenoviral (HDAd) vectors that are devoid of all viral coding sequences are attractive vectors for gene therapy because they efficiently transduce a variety of cell types, have a large cloning capacity, have low risks of insertional carcinogenesis, and drive long-term transgene expression without chronic toxicity. The main limitation of HDAd vectors is the host innate inflammatory response elicited by capsid proteins that occurs shortly after intravascular administration and result in dose-dependent acute toxicity. Major efforts focused on elucidating adenoviral vector–host interactions have unraveled multiple factors involved in the acute toxicity. In this chapter, we provide a review of the most significant and advanced studies on the strategies to overcome the issue of acute toxicity and on the applications of these vectors for gene therapy of inherited diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Alba R, Hearing P, Bosch A, Chillon M. Differential amplification of adenovirus vectors by flanking the packaging signal with attB/attP-PhiC31 sequences: implications for helper-dependent adenovirus production. Virology. 2007;367:51–8.

    Article  CAS  PubMed  Google Scholar 

  2. Ng P, Beauchamp C, Evelegh C, Parks R, Graham FL. Development of a FLP/frt system for generating helper-dependent adenoviral vectors. Mol Ther. 2001;3:809–15.

    Article  CAS  PubMed  Google Scholar 

  3. Sargent KL, Ng P, Evelegh C, Graham FL, Parks RJ. Development of a size-restricted pIX-deleted helper virus for amplification of helper-dependent adenovirus vectors. Gene Ther. 2004;11:504–11.

    Article  CAS  PubMed  Google Scholar 

  4. Umana P, Gerdes CA, Stone D, Davis JR, Ward D, Castro MG, Lowenstein PR. Efficient FLPe recombinase enables scalable production of helper-dependent adenoviral vectors with negligible helper-virus contamination. Nat Biotechnol. 2001;19:582–5.

    Article  CAS  PubMed  Google Scholar 

  5. Parks RJ, Chen L, Anton M, Sankar U, Rudnicki MA, Graham FL. A helper-dependent adenovirus vector system: removal of helper virus by cre-mediated excision of the viral packaging signal. Proc Natl Acad Sci USA. 1996;93:13565–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sandig V, Youil R, Bett AJ, Franlin LL, Oshima M, Maione D, Wang F, et al. Optimization of the helper-dependent adenovirus system for production and potency in vivo. Proc Natl Acad Sci USA. 2000;97:1002–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Parks RJ, Graham FL. A helper-dependent system for adenovirus vector production helps define a lower limit for efficient DNA packaging. J Virol. 1997;71:3293–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bett AJ, Prevec L, Graham FL. Packaging capacity and stability of human adenovirus type 5 vectors. J Virol. 1993;67:5911–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Schiedner G, Hertel S, Johnston M, Biermann V, Dries V, Kochanek S. Variables affecting in vivo performance of high-capacity adenovirus vectors. J Virol. 2002;76:1600–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kim IH, Jozkowicz A, Piedra PA, Oka K, Chan L. Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector. Proc Natl Acad Sci USA. 2001;98:13282–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schiedner G, Morral N, Parks RJ, Wu Y, Koopmans SC, Langston C, Graham FL, et al. Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nat Genet. 1998;18:180–3.

    Article  CAS  PubMed  Google Scholar 

  12. Palmer D, Ng P. Improved system for helper-dependent adenoviral vector production. Mol Ther. 2003;8:846–52.

    Article  CAS  PubMed  Google Scholar 

  13. Parks R, Evelegh C, Graham F. Use of helper-dependent adenoviral vectors of alternative serotypes permits repeat vector administration. Gene Ther. 1999;6:1565–73.

    Article  CAS  PubMed  Google Scholar 

  14. Weaver EA, Nehete PN, Buchl SS, Senac JS, Palmer D, Ng P, Sastry KJ, et al. Comparison of replication-competent, first generation, and helper-dependent adenoviral vaccines. PLoS ONE. 2009;4:e5059.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Weaver EA, Nehete PN, Nehete BP, Buchl SJ, Palmer D, Montefiori DC, Ng P, et al. Protection against mucosal SHIV challenge by peptide and helper-dependent adenovirus vaccines. Viruses. 2009;1:920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Brunetti-Pierri N, Ng P. Helper-dependent adenoviral vectors for liver-directed gene therapy. Hum Mol Genet. 2011;20:R7–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Brunetti-Pierri N, Palmer DJ, Beaudet AL, Carey KD, Finegold M, Ng P. Acute toxicity after high-dose systemic injection of helper-dependent adenoviral vectors into nonhuman primates. Hum Gene Ther. 2004;15:35–46.

    Article  CAS  PubMed  Google Scholar 

  18. Morral N, O’Neal WK, Rice K, Leland MM, Piedra PA, Aguilar-Cordova E, Carey KD, et al. Lethal toxicity, severe endothelial injury, and a threshold effect with high doses of an adenoviral vector in baboons. Hum Gene Ther. 2002;13:143–54.

    Article  CAS  PubMed  Google Scholar 

  19. Lozier JN, Csako G, Mondoro TH, Krizek DM, Metzger ME, Costello R. Toxicity of a first-generation adenoviral vector in rhesus m acaques. Hum Gene Ther. 2002;13:113–24.

    Article  CAS  PubMed  Google Scholar 

  20. Muruve DA, Barnes MJ, Stillman IE, Libermann TA. Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. Hum Gene Ther. 1999;10:965–76.

    Article  CAS  PubMed  Google Scholar 

  21. Schnell MA, Zhang Y, Tazelaar J, Gao GP, Yu QC, Qian R, Chen SJ, et al. Activation of innate immunity in nonhuman primates following intraportal administration of adenoviral vectors. Mol Ther. 2001;3:708–22.

    Article  CAS  PubMed  Google Scholar 

  22. Liu Q, Muruve DA. Molecular basis of the inflammatory response to adenovirus vectors. Gene Ther. 2003;10:935–40.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang Y, Chirmule N, Gao GP, Qian R, Croyle M, Joshi B, Tazelaar J, et al. Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages. Mol Ther. 2001;3:697–707.

    Article  CAS  PubMed  Google Scholar 

  24. Xu Z, Smith JS, Tian J, Byrnes AP. Induction of shock after intravenous injection of adenovirus vectors: a critical role for platelet-activating factor. Mol Ther. 2010;18:609–16.

    Article  CAS  PubMed  Google Scholar 

  25. Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, Wilson JM, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab. 2003;80:148–58.

    Article  CAS  PubMed  Google Scholar 

  26. Cichon G, Boeckh-Herwig S, Schmidt HH, Wehnes E, Muller T, Pring-Akerblom P, Burger R. Complement activation by recombinant adenoviruses. Gene Ther. 2001;8:1794–800.

    Article  CAS  PubMed  Google Scholar 

  27. Varnavski AN, Zhang Y, Schnell M, Tazelaar J, Louboutin JP, Yu QC, Bagg A, et al. Preexisting immunity to adenovirus in rhesus monkeys fails to prevent vector-induced toxicity. J Virol. 2002;76:5711–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tao N, Gao GP, Parr M, Johnston J, Baradet T, Wilson JM, Barsoum J, et al. Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver. Mol Ther. 2001;3:28–35.

    Article  CAS  PubMed  Google Scholar 

  29. Schiedner G, Hertel S, Johnston M, Dries V, van Rooijen N, Kochanek S. Selective depletion or blockade of Kupffer cells leads to enhanced and prolonged hepatic transgene expression using high-capacity adenoviral vectors. Mol Ther. 2003;7:35–43.

    Article  CAS  PubMed  Google Scholar 

  30. Jiang H, Wang Z, Serra D, Frank MM, Amalfitano A. Recombinant adenovirus vectors activate the alternative complement pathway, leading to the binding of human complement protein C3 independent of anti-ad antibodies. Mol Ther. 2004;10:1140–2.

    Article  CAS  PubMed  Google Scholar 

  31. Kiang A, Hartman ZC, Everett RS, Serra D, Jiang H, Frank MM, Amalfitano A. Multiple innate inflammatory responses induced after systemic adenovirus vector delivery depend on a functional complement system. Mol Ther. 2006;14:588–98.

    Article  CAS  PubMed  Google Scholar 

  32. Doronin K, Flatt JW, Di Paolo NC, Khare R, Kalyuzhniy O, Acchione M, Sumida JP, et al. Coagulation factor X activates innate immunity to human species C adenovirus. Science. 2012;338:795–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Piccolo P, Vetrini F, Mithbaokar P, Grove NC, Bertin T, Palmer D, Ng P, et al. SR-A and SREC-I are Kupffer and endothelial cell receptors for helper-dependent adenoviral vectors. Mol Ther. 2013;21:767–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Haisma HJ, Boesjes M, Beerens AM, van der Strate BW, Curiel DT, Pluddemann A, Gordon S, et al. Scavenger receptor A: a new route for adenovirus 5. Mol Pharm. 2009;6:366–74.

    Article  CAS  PubMed  Google Scholar 

  35. Khare R, Reddy VS, Nemerow GR, Barry MA. Identification of adenovirus serotype 5 hexon regions that interact with scavenger receptors. J Virol. 2012;86:2293–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lievens J, Snoeys J, Vekemans K, Van Linthout S, de Zanger R, Collen D, Wisse E, et al. The size of sinusoidal fenestrae is a critical determinant of hepatocyte transduction after adenoviral gene transfer. Gene Ther. 2004;11:1523–31.

    Article  CAS  PubMed  Google Scholar 

  37. Snoeys J, Lievens J, Wisse E, Jacobs F, Duimel H, Collen D, Frederik P, et al. Species differences in transgene DNA uptake in hepatocytes after adenoviral transfer correlate with the size of endothelial fenestrae. Gene Ther. 2007;14:604–12.

    Article  CAS  PubMed  Google Scholar 

  38. Wisse E, Jacobs F, Topal B, Frederik P, De Geest B. The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer. Gene Ther. 2008;15:1193–9.

    Article  CAS  PubMed  Google Scholar 

  39. Jager L, Ehrhardt A. Persistence of high-capacity adenoviral vectors as replication-defective monomeric genomes in vitro and in murine liver. Hum Gene Ther. 2009;20:883–96.

    Article  CAS  PubMed  Google Scholar 

  40. Kreppel F, Kochanek S. Long-term transgene expression in proliferating cells mediated by episomally maintained high-capacity adenovirus vectors. J Virol. 2004;78:9–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ross PJ, Kennedy MA, Parks RJ. Host cell detection of noncoding stuffer DNA contained in helper-dependent adenovirus vectors leads to epigenetic repression of transgene expression. J Virol. 2009;83:8409–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ross PJ, Kennedy MA, Christou C, Quiroz MR, Poulin KL, Parks RJ. Assembly of helper-dependent adenovirus DNA into chromatin promotes efficient gene expression. J Virol. 2011;85:3950–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Harui A, Suzuki S, Kochanek S, Mitani K. Frequency and stability of chromosomal integration of adenovirus vectors. J Virol. 1999;73:6141–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Stephen SL, Sivanandam VG, Kochanek S. Homologous and heterologous recombination between adenovirus vector DNA and chromosomal DNA. J Gene Med. 2008;10:1176–89.

    Article  CAS  PubMed  Google Scholar 

  45. Hillgenberg M, Tonnies H, Strauss M. Chromosomal integration pattern of a helper-dependent minimal adenovirus vector with a selectable marker inserted into a 27.4-kilobase genomic stuffer. J Virol. 2001;75:9896–908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ohbayashi F, Balamotis MA, Kishimoto A, Aizawa E, Diaz A, Hasty P, Graham FL, et al. Correction of chromosomal mutation and random integration in embryonic stem cells with helper-dependent adenoviral vectors. Proc Natl Acad Sci USA. 2005;102:13628–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Suzuki K, Mitsui K, Aizawa E, Hasegawa K, Kawase E, Yamagishi T, Shimizu Y, et al. Highly efficient transient gene expression and gene targeting in primate embryonic stem cells with helper-dependent adenoviral vectors. Proc Natl Acad Sci USA. 2008;105:13781–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Stephen SL, Montini E, Sivanandam VG, Al-Dhalimy M, Kestler HA, Finegold M, Grompe M, et al. Chromosomal integration of adenoviral vector DNA in vivo. J Virol. 2010;84:9987–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mitrani E, Pearlman A, Stern B, Miari R, Goltsman H, Kunicher N, Panet A. Biopump: autologous skin-derived micro-organ genetically engineered to provide sustained continuous secretion of therapeutic proteins. Dermatol Ther. 2011;24:489–97.

    Article  PubMed  Google Scholar 

  50. Shapir N, Miari R, Blum S, Schwartz D, Chernin G, Neil GA, Afik D, et al. Preclinical and preliminary clinical evaluation of genetically transduced dermal tissue implants for the sustained secretion of erythropoietin and interferon alpha. Hum Gene Ther Clin Dev. 2015;26:216–27.

    Article  CAS  PubMed  Google Scholar 

  51. White GI, Monahan PE. Gene therapy for hemophilia A. Oxford, UK: Blackwell Publishing Ltd.; 2007.

    Google Scholar 

  52. Brunetti-Pierri N, Ng T, Iannitti DA, Palmer DJ, Beaudet AL, Finegold MJ, Carey KD, et al. Improved hepatic transduction, reduced systemic vector dissemination, and long-term transgene expression by delivering helper-dependent adenoviral vectors into the surgically isolated liver of nonhuman primates. Hum Gene Ther. 2006;17:391–404.

    Article  CAS  PubMed  Google Scholar 

  53. Schmitt F, Pastore N, Abarrategui-Pontes C, Flageul M, Myara A, Laplanche S, Labrune P, et al. Correction of hyperbilirubinemia in Gunn rats by surgical delivery of low doses of helper-dependent adenoviral vectors. Hum Gene Ther Methods. 2014;25:181–6.

    Article  CAS  PubMed  Google Scholar 

  54. Brunetti-Pierri N, Stapleton GE, Law M, Breinholt J, Palmer DJ, Zuo Y, Grove NC, et al. Efficient, long-term hepatic gene transfer using clinically relevant HDAd doses by balloon occlusion catheter delivery in nonhuman primates. Mol Ther. 2009;17:327–33.

    Article  CAS  PubMed  Google Scholar 

  55. Brunetti-Pierri N, Liou A, Patel P, Palmer D, Grove N, Finegold M, Piccolo P, et al. Balloon catheter delivery of helper-dependent adenoviral vector results in sustained, therapeutic hFIX expression in rhesus macaques. Mol Ther. 2012;20:1863–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rastall DP, Seregin SS, Aldhamen YA, Kaiser LM, Mullins C, Liou A, Ing F, et al. Long-term, high-level hepatic secretion of acid alpha-glucosidase for Pompe disease achieved in non-human primates using helper-dependent adenovirus. Gene Ther. 2016;23:743–52.

    Article  CAS  PubMed  Google Scholar 

  57. Oka K, Mullins CE, Kushwaha RS, Leen AM, Chan L. Gene therapy for rhesus monkeys heterozygous for LDL receptor deficiency by balloon catheter hepatic delivery of helper-dependent adenoviral vector. Gene Ther. 2015;22:87–95.

    Article  CAS  PubMed  Google Scholar 

  58. Martin LJ, Mahaney MC, Bronikowski AM, Dee Carey K, Dyke B, Comuzzie AG. Lifespan in captive baboons is heritable. Mech Ageing Dev. 2002;123:1461–7.

    Article  PubMed  Google Scholar 

  59. Brunetti-Pierri N, Ng T, Iannitti D, Cioffi W, Stapleton G, Law M, Breinholt J, et al. Transgene expression up to 7 years in nonhuman primates following hepatic transduction with helper-dependent adenoviral vectors. Hum Gene Ther. 2013;24:761–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sung MW, Chen SH, Thung SN, Zhang DY, Huang TG, Mandeli JP, Woo SL. Intratumoral delivery of adenovirus-mediated interleukin-12 gene in mice with metastatic cancer in the liver. Hum Gene Ther. 2002;13:731–43.

    Article  CAS  PubMed  Google Scholar 

  61. Pastore N, Nusco E, Piccolo P, Castaldo S, Vanikova J, Vetrini F, Palmer DJ, et al. Improved efficacy and reduced toxicity by ultrasound-guided intrahepatic injections of helper-dependent adenoviral vector in Gunn rats. Hum Gene Ther Methods. 2013;24:321–7.

    Article  CAS  PubMed  Google Scholar 

  62. Wolff G, Worgall S, van Rooijen N, Song WR, Harvey BG, Crystal RG. Enhancement of in vivo adenovirus-mediated gene transfer and expression by prior depletion of tissue macrophages in the target organ. J Virol. 1997;71:624–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Salkowski CA, Neta R, Wynn TA, Strassmann G, van Rooijen N, Vogel SN. Effect of liposome-mediated macrophage depletion on LPS-induced cytokine gene expression and radioprotection. J Immunol. 1995;155:3168–79.

    CAS  PubMed  Google Scholar 

  64. Callery MP, Kamei T, Flye MW. Kupffer cell blockade increases mortality during intra-abdominal sepsis despite improving systemic immunity. Arch Surg. 1990;125:36–40 (discussion 40-31).

    Google Scholar 

  65. Ishiyama H, Sato M, Matsumura K, Sento M, Ogino K, Hobara T. Proliferation of hepatocytes and attenuation from carbon tetrachloride hepatotoxicity by gadolinium chloride in rats. Pharmacol Toxicol. 1995;77:293–8.

    Article  CAS  PubMed  Google Scholar 

  66. Haisma HJ, Kamps JA, Kamps GK, Plantinga JA, Rots MG, Bellu AR. Polyinosinic acid enhances delivery of adenovirus vectors in vivo by preventing sequestration in liver macrophages. J Gen Virol. 2008;89:1097–105.

    Article  CAS  PubMed  Google Scholar 

  67. Xu Z, Tian J, Smith JS, Byrnes AP. Clearance of adenovirus by Kupffer cells is mediated by scavenger receptors, natural antibodies, and complement. J Virol. 2008;82:11705–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Piccolo P, Annunziata P, Mithbaokar P, Brunetti-Pierri N. SR-A and SREC-I binding peptides increase HDAd-mediated liver transduction. Gene Ther. 2014;21:950–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Prill JM, Espenlaub S, Samen U, Engler T, Schmidt E, Vetrini F, Rosewell A, et al. Modifications of adenovirus hexon allow for either hepatocyte detargeting or targeting with potential evasion from Kupffer cells. Mol Ther. 2011;19:83–92.

    Article  CAS  PubMed  Google Scholar 

  70. Hofherr SE, Shashkova EV, Weaver EA, Khare R, Barry MA. Modification of adenoviral vectors with polyethylene glycol modulates in vivo tissue tropism and gene expression. Mol Ther. 2008;16:1276–82.

    Article  CAS  PubMed  Google Scholar 

  71. Mok H, Palmer DJ, Ng P, Barry MA. Evaluation of polyethylene glycol modification of first-generation and helper-dependent adenoviral vectors to reduce innate immune responses. Mol Ther. 2005;11:66–79.

    Article  CAS  PubMed  Google Scholar 

  72. Croyle MA, Le HT, Linse KD, Cerullo V, Toietta G, Beaudet A, Pastore L. PEGylated helper-dependent adenoviral vectors: highly efficient vectors with an enhanced safety profile. Gene Ther. 2005;12:579–87.

    Article  CAS  PubMed  Google Scholar 

  73. Leggiero E, Astone D, Cerullo V, Lombardo B, Mazzaccara C, Labruna G, Sacchetti L, et al. PEGylated helper-dependent adenoviral vector expressing human Apo A-I for gene therapy in LDLR-deficient mice. Gene Ther. 2013.

    Google Scholar 

  74. Xu Z, Qiu Q, Tian J, Smith JS, Conenello GM, Morita T, Byrnes AP. Coagulation factor X shields adenovirus type 5 from attack by natural antibodies and complement. Nat Med. 2013;19:452–7.

    Article  CAS  PubMed  Google Scholar 

  75. Krutzke L, Prill JM, Engler T, Schmidt CQ, Xu Z, Byrnes AP, Simmet T, et al. Substitution of blood coagulation factor X-binding to Ad5 by position-specific PEGylation: preventing vector clearance and preserving infectivity. J Control Release. 2016;235:379–92.

    Article  CAS  PubMed  Google Scholar 

  76. Khare R, May SM, Vetrini F, Weaver EA, Palmer D, Rosewell A, Grove N, et al. Generation of a Kupffer cell-evading adenovirus for systemic and liver-directed gene transfer. Mol Ther. 2011;19:1254–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wonganan P, Clemens CC, Brasky K, Pastore L, Croyle MA. Species differences in the pharmacology and toxicology of pegylated helper-dependent adenovirus. Mol Pharm. 2010.

    Google Scholar 

  78. Yang Y, Nunes FA, Berencsi K, Furth EE, Gonczol E, Wilson JM. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci USA. 1994;91:4407–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Dai Y, Schwarz EM, Gu D, Zhang WW, Sarvetnick N, Verma IM. Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: tolerization of factor IX and vector antigens allows for long-term expression. Proc Natl Acad Sci USA. 1995;92:1401–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Morral N, O’Neal W, Zhou H, Langston C, Beaudet A. Immune responses to reporter proteins and high viral dose limit duration of expression with adenoviral vectors: comparison of E2a wild type and E2a deleted vectors. Hum Gene Ther. 1997;8:1275–86.

    Article  CAS  PubMed  Google Scholar 

  81. O’Neal WK, Zhou H, Morral N, Aguilar-Cordova E, Pestaner J, Langston C, Mull B, et al. Toxicological comparison of E2a-deleted and first-generation adenoviral vectors expressing alpha1-antitrypsin after systemic delivery. Hum Gene Ther. 1998;9:1587–98.

    Article  PubMed  Google Scholar 

  82. Yang Y, Li Q, Ertl HC, Wilson JM. Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J Virol. 1995;69:2004–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Yang Y, Xiang Z, Ertl HC, Wilson JM. Upregulation of class I major histocompatibility complex antigens by interferon gamma is necessary for T-cell-mediated elimination of recombinant adenovirus-infected hepatocytes in vivo. Proc Natl Acad Sci USA. 1995;92:7257–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Joseph PM, O’Sullivan BP, Lapey A, Dorkin H, Oren J, Balfour R, Perricone MA, et al. Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. I. Methods, safety, and clinical implications. Hum Gene Ther. 2001;12:1369–82.

    Article  CAS  PubMed  Google Scholar 

  85. Simon RH, Engelhardt JF, Yang Y, Zepeda M, Weber-Pendleton S, Grossman M, Wilson JM. Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: toxicity study. Hum Gene Ther. 1993;4:771–80.

    Article  CAS  PubMed  Google Scholar 

  86. Yei S, Mittereder N, Wert S, Whitsett JA, Wilmott RW, Trapnell BC. In vivo evaluation of the safety of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator cDNA to the lung. Hum Gene Ther. 1994;5:731–44.

    Article  CAS  PubMed  Google Scholar 

  87. Wilmott RW, Amin RS, Perez CR, Wert SE, Keller G, Boivin GP, Hirsch R, et al. Safety of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator cDNA to the lungs of nonhuman primates. Hum Gene Ther. 1996;7:301–18.

    Article  CAS  PubMed  Google Scholar 

  88. Harvey BG, Maroni J, O’Donoghue KA, Chu KW, Muscat JC, Pippo AL, Wright CE, et al. Safety of local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions. Hum Gene Ther. 2002;13:15–63.

    Article  CAS  PubMed  Google Scholar 

  89. Toietta G, Koehler DR, Finegold MJ, Lee B, Hu J, Beaudet AL. Reduced inflammation and improved airway expression using helper-dependent adenoviral vectors with a K18 promoter. Mol Ther. 2003;7:649–58.

    Article  CAS  PubMed  Google Scholar 

  90. Koehler DR, Hannam V, Belcastro R, Steer B, Wen Y, Post M, Downey G, et al. Targeting transgene expression for cystic fibrosis gene therapy. Mol Ther. 2001;4:58–65.

    Article  CAS  PubMed  Google Scholar 

  91. O’Neal WK, Rose E, Zhou H, Langston C, Rice K, Carey D, Beaudet AL. Multiple advantages of alpha-fetoprotein as a marker for in vivo gene transfer. Mol Ther. 2000;2:640–8.

    Article  PubMed  Google Scholar 

  92. Koehler DR, Frndova H, Leung K, Louca E, Palmer D, Ng P, McKerlie C, et al. Aerosol delivery of an enhanced helper-dependent adenovirus formulation to rabbit lung using an intratracheal catheter. J Gene Med. 2005;7:1409–20.

    Article  CAS  PubMed  Google Scholar 

  93. Cao H, Machuca TN, Yeung JC, Wu J, Du K, Duan C, Hashimoto K, et al. Efficient gene delivery to pig airway epithelia and submucosal glands using helper-dependent adenoviral vectors. Mol Ther Nucleic Acids. 2013;2:e127.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, Ozelo MC, et al. Successful transduction of liver in hemophilia by AAV-factor IX and limitations imposed by the host immune response. Nat Med. 2006;12:342–7.

    Article  CAS  PubMed  Google Scholar 

  95. Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, Chowdary P, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365:2357–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Donsante A, Miller DG, Li Y, Vogler C, Brunt EM, Russell DW, Sands MS. AAV vector integration sites in mouse hepatocellular carcinoma. Science. 2007;317:477.

    Article  CAS  PubMed  Google Scholar 

  97. Chandler RJ, LaFave MC, Varshney GK, Trivedi NS, Carrillo-Carrasco N, Senac JS, Wu W, et al. Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J Clin Invest. 2015;125:870–80.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Reiss J, Hahnewald R. Molybdenum cofactor deficiency: mutations in GPHN, MOCS1, and MOCS2. Hum Mutat. 2011;32:10–8.

    Article  CAS  PubMed  Google Scholar 

  99. Nault JC, Datta S, Imbeaud S, Franconi A, Mallet M, Couchy G, Letouze E, et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet. 2015;47:1187–93.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078, Pozzuoli (Napoli), Italy

    Pasquale Piccolo & Nicola Brunetti-Pierri

  2. Department of Translational Medicine, Federico II University of Naples, Naples, Italy

    Nicola Brunetti-Pierri

Authors
  1. Pasquale Piccolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicola Brunetti-Pierri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicola Brunetti-Pierri .

Editor information

Editors and Affiliations

  1. Department of Translational Medicine, University of Naples Federico II, Naples, Italy

    Nicola Brunetti-Pierri

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Piccolo, P., Brunetti-Pierri, N. (2017). Helper-Dependent Adenoviral Vectors for Gene Therapy of Inherited Diseases. In: Brunetti-Pierri, N. (eds) Safety and Efficacy of Gene-Based Therapeutics for Inherited Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-53457-2_4

Download citation

Publish with us

Policies and ethics

Search

Navigation