Skip to main content
SpringerLink
Log in

Toxicity Associated with Repeated Administration of First-Generation Adenovirus Vectors Does Not Occur with a Helper-Dependent Vector

  • Review Article
  • Published:
Molecular Medicine Aims and scope Submit manuscript

Abstract

Background

Certain gene therapy protocols may require multiple administrations of vectors to achieve therapeutic benefit to the patient. This may be especially relevant for vectors such as adenoviral vectors that do not integrate into the host chromosome. Because immunocompetent animal models used for gene transfer studies develop neutralizing antibodies to adenoviral vectors after a single administration, little is known about how repeat administrations of vectors might affect transgene expression and vector toxicity.

Materials and Methods

We used mice deficient in the membrane spanning region of immunoglobulin (IgM), which do not develop antibodies, to evaluate the effect of repeated intravenous administration of first-generation and helper-dependent adenoviral vectors expressing human α1-antitrypsin (hAAT). The duration and levels of transgene expression were evaluated after repeated administration of vectors. Toxicity was assessed by measuring the level of liver enzymes in the serum and the degrees of hepatocyte hypertrophy and proliferation.

Results

We found that previous administration of first-generation adenoviral vectors can alter the response to subsequent doses. These alterations included an increase in transgene expression early (within 1 and 3 days), followed by a rapid drop in expression by day 7. In addition, previous administrations of first-generation vectors led to an increase in toxicity of subsequent doses, as indicated by a rise in liver enzymes and an increase in hepatocyte proliferation. In contrast to first-generation vectors, use of the helper-dependent adenovirus vector, AdSTK109, which contained no viral coding regions, did not lead to increased toxicity after multiple administrations.

Conclusions

We conclude that the response of the host to adenoviral vectors can be altered after repeated administration, compared with the response after the initial vector dose. In addition, these experiments provide further evidence for the relative safety of helper-dependent adenoviral vectors for gene therapy, compared with first-generation vectors.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Graham FL, Prevec L. (1992) Adenovirus-based expression vectors and recombinant vaccines. In: Ellis RW (ed.). Vaccines: New Approaches in Immunological Problems. Butterworth-Heinemann, Boston, MA. pp. 363–390.

    Chapter  Google Scholar 

  2. Berkner KL. (1988) Development of adenovirus vectors for the expression of heterologous genes. BioTechniques 6: 616–629.

    PubMed  CAS  Google Scholar 

  3. Graham FL, Prevec L. (1995) Methods for construction of adenovirus vectors. Mol. Biotech. 3: 207–220.

    Article  CAS  Google Scholar 

  4. Kaplan JM, St. George JA, Pennington SE, et al. (1996) Humoral and cellular immune responses of nonhuman primates to long-term repeated lung exposure to Ad2/CFTR-2. Gene Therapy 3: 117–127.

    PubMed  CAS  Google Scholar 

  5. Kozarsky KF, McKinley DR, Austin LL, et al. (1994) In vivo correction of low density lipoprotein receptor deficiency in the Watanabe heritable hyperlipidemic rabbit with recombinant adenoviruses. J. Biol. Chem. 269: 13695–13702.

    PubMed  CAS  Google Scholar 

  6. Yei S, Mittereder N, Tang K, O’Sullivan C, Trapnell BC. (1994) Adenovirus-mediated gene transfer for cystic fibrosis: quantitative evaluation of repeated in vivo vector administration to the lung. Gene Therapy 1: 192–200.

    PubMed  CAS  Google Scholar 

  7. Yang Y, Ertl HCJ, Wilson JM. (1994) MHC class I-restricted cytotoxic T lymphocytes to viral antigens destroy hepatocytes in mice infected with E1-deleted recombinant adenoviruses. Immunity 1: 433–442.

    Article  CAS  Google Scholar 

  8. Yang Y, Nunes FA, Berencsi K, et al. (1994) Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc. Natl. Acad. Sci. U.S.A. 91: 4407–4411.

    Article  CAS  Google Scholar 

  9. Yang Y, Li Q, Ertl HCJ, Wilson JM. (1995) Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J. Virol. 69: 2004–2015.

    PubMed  PubMed Central  CAS  Google Scholar 

  10. Yang Y, Su Q, Wilson JM. (1996) Role of viral antigens in destructive cellular immune responses to adenovirus vector-transduced cells in mouse lungs. J. Virol. 70: 7209–7212.

    PubMed  PubMed Central  CAS  Google Scholar 

  11. Dai Y, Schwarz EM, Gu D, et al. (1995) 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. U.S.A. 92: 1401–1405.

    Article  CAS  Google Scholar 

  12. Morral N, O’Neal WK, Zhou H, Langston C, Beaudet A. (1997) 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. 8: 1275–1286.

    Article  CAS  Google Scholar 

  13. Tripathy SK, Black HB, Goldwasser E, Leiden JM. (1996) Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nat. Med. 2: 545–550.

    Article  CAS  Google Scholar 

  14. Van Ginkel FW, Liu C, Simecka JW, et al. (1995) Intratracheal gene delivery with adenoviral vector induces elevated systemic IgG and mucosal IgA antibodies to adenovirus and β-galactosidase. Hum. Gene Ther. 6: 895–903.

    Article  Google Scholar 

  15. Michou AI, Santoro L, Christ M, et al. (1997) Adenovirus-mediated gene transfer: influence of transgene, mouse stratin ant type of immune response on persistence of transgene expression. Gene Therapy 4: 473–482.

    Article  CAS  Google Scholar 

  16. Morral N, Parks RJ, Zhou H, et al. (1998) High doses of a helper-dependent adenoviral vector yield supraphysiological levels of α1-antitrypsin with negligible toxicity. Hum. Gene Ther. 9: 2709–2716.

    Article  CAS  Google Scholar 

  17. Grubb BR, Pickles RJ, Ye H, et al. (1994) Inefficient gene transfer by adenovirus vector to cystic fibrosis airway epithelia of mice and humans. Nature 371: 802–806.

    Article  CAS  Google Scholar 

  18. Knowles MR, Hohneker KW, Zhou Z, et al. (1995) A controlled study of adenoviral vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis [see comments]. N. Engl. J. Med. 333: 823–831.

    Article  CAS  Google Scholar 

  19. Connelly S, Gardner JM, Lyons RM, McClelland A, Kaleko M. (1996) Sustained expression of therapeutic levels of human factor VIII in mice. Blood 87: 4671–4677.

    PubMed  CAS  Google Scholar 

  20. Armentano D, Sookdeo CC, Hehir KM, et al. (1995) Characterization of an adenovirus gene transfer vector containing an E4 deletion. Hum. Gene Ther. 6: 1343–1353.

    Article  CAS  Google Scholar 

  21. Yeh P, Dedieu JF, Orsini C, et al. (1996) Efficient dual transcomplementation of adenovirus E1 and E4 regions from a 293-derived cell line expressing a minimal E4 functional unit. J. Virol. 70: 559–565.

    PubMed  PubMed Central  CAS  Google Scholar 

  22. Brough DE, Lizonova A, Hsu C, Kulesa VA, Kovesdi I. (1996) A gene transfer vector-cell line system for complete functional complementation of adenovirus early regions E1 and E4. J. Virol. 70: 6497–6501.

    PubMed  PubMed Central  CAS  Google Scholar 

  23. Engelhardt JF, Ye X, Doranz B, Wilson JM. (1994) Ablation of E2A in recombinant adenoviruses improves transgene persistence and decreases inflammatory response in mouse liver. Proc. Natl. Acad. Sci. U.S.A. 91: 6196–6200.

    Article  CAS  Google Scholar 

  24. Gao G-P, Yang Y, Wilson JM. (1996) Biology of adenovirus vectors with E1 and E4 deletions for liver-directed gene therapy. J. Virol. 70: 8934–8943.

    PubMed  PubMed Central  CAS  Google Scholar 

  25. Gorziglia MI, Kadan MJ, Yei S, et al. (1996) Elimination of both E1 and E2a from adenovirus vectors further improves prospects for in vivo human gene therapy. J. Virol. 70: 4173–4178.

    PubMed  PubMed Central  CAS  Google Scholar 

  26. Krougliak V, Graham FL. (1995) Development of cell lines capable of complementing E1, E4, and protein IX defective adenovirus type 5 mutants. Hum. Gene Ther. 6: 1575–1586.

    Article  CAS  Google Scholar 

  27. Wang Q, Jia X-C, Finer MH. (1995) A packaging cell line for propagation of recombinant adenovirus vectors containing two lethal gene-region deletion. Gene Therapy 2: 775–783.

    PubMed  CAS  Google Scholar 

  28. Yang Y, Nunes FA, Berencsi K, et al. (1994) Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis. Nat. Genet. 7: 362–369.

    Article  CAS  Google Scholar 

  29. Zhou H, O’Neal WK, Morral N, Beaudet AL. (1996) Development of a complementing cell line and a system for construction of adenovirus vectors with E1 and E2a deleted. J. Virol. 70: 7030–7038.

    PubMed  PubMed Central  CAS  Google Scholar 

  30. Engelhardt JF, Litzky L, Wilson JM. (1994) Prolonged transgene expression in cotton rat lung with recombinant adenoviruses defective in E2a. Hum. Gene Ther. 5: 1217–1229.

    Article  CAS  Google Scholar 

  31. Goldman MJ, Litzky LA, Engelhardt JF, Wilson JM. (1995) Transfer of the CFTR gene to the lung of nonhuman primates with E1-deleted, E2a-defective recombinant adenoviruses: a preclinical toxicology study. Hum. Gene Ther. 6: 839–851.

    Article  CAS  Google Scholar 

  32. Dedieu J-F, Vigne E, Torrent C, et al. (1997) Long-term gene delivery into the livers of immunocompetent mice with E1/E4-defective adenoviruses. J. Virol. 71: 4626–4637.

    PubMed  PubMed Central  CAS  Google Scholar 

  33. Wang Q, Greenburg G, Bunch D, Farson D, Finer MH. (1997) Persistent transgene expression in mouse liver following gene transfer with a DE1/DE4 adenovirus vector. Gene Therapy 4: 393–400.

    Article  CAS  Google Scholar 

  34. O’Neal WK, Zhou H, Morral N, et al. (1998) Toxicological comparison of E2a-deleted and first generation adenoviral vectors expressin α1- antitrypsin after systemic delivery. Hum. Gene Ther. 9: 1587–1598.

    Article  Google Scholar 

  35. Fang B, Wang H, Gordon G, et al. (1996) Lack of persistence of E1- recombinant adenoviral vectors containing a temperature-sensitive E2a mutation in immunocompetent mice and hemophilia B dogs. Gene Therapy 3: 217–222.

    PubMed  CAS  Google Scholar 

  36. Lusky M, Rittner K, Dieterle A, et al. (1998) In vitro and in vivo biology of recombinant adenovirus vectors with E1, E1/E2A or E1/E4 deleted. J. Virol. 72: 2022–2032.

    PubMed  PubMed Central  CAS  Google Scholar 

  37. Schiedner G, Morral N, Parks RJ, et al. (1998) Genomic DNA transfer with a high capacity adenoviral vector that has all viral genes deleted results in improved in vivo gene expression and decreased toxicity. Nat. Genet. 18: 180–183.

    Article  CAS  Google Scholar 

  38. Morsy MA, Gu MC, Motzel S, et al. (1998) An adenoviral vector deleted for all viral coding sequences results in enhanced safety and extended expression of a leptin transgene. Proc. Natl. Acad. Sci. U.S.A. 95: 7866–7871.

    Article  CAS  Google Scholar 

  39. Morsy MA, Caskey CT. (1998) Helper dependent adenoviral vectors-improved safety and expression. Biogenic Amines 14: 433–449.

    CAS  Google Scholar 

  40. Chen HH, Mack LM, Kelly R, et al. (1997) Persistence in muscle of an adenoviral vector that lacks all viral genes. Proc. Natl. Acad. Sci. U.S.A. 94: 1645–1650.

    Article  CAS  Google Scholar 

  41. Kay MA, Holterman AX, Meuse L, et al. (1995) Long-term hepatic adenovirus-mediated gene expression in mice following CTLA4Ig administration. Nat. Genet. 11: 191–197.

    Article  CAS  Google Scholar 

  42. Yang YP, Su Q, Grewal IS, et al. (1996) Transient subversion of cd40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues. J. Virol. 70: 6370–6377.

    PubMed  PubMed Central  CAS  Google Scholar 

  43. Yang Y, Trinchieri G, Wilson JM. (1995) Recombinant IL-12 prevents formation of blocking IgA antibodies to recombinant adenovirus and allows repeated gene therapy to mouse lung. Nat. Med. 1: 890–893.

    Article  CAS  Google Scholar 

  44. Smith T, White BD, Gardner JM, Kaleko M, Mcclelland A. (1996) Transient immunosuppression permits successful repetitive intravenous administration of an adenovirus vector. Gene Therapy 3: 496–502.

    PubMed  CAS  Google Scholar 

  45. Lochmuller H, Petrof BJ, Allen C, et al. (1995) Immunosuppression by FK506 markedly prolongs expression of adenovirus-delivered transgene in skeletal muscles of adult dystrophic [mdx] mice. Biochem. Biophys. Res. Comm. 213: 569–574.

    Article  CAS  Google Scholar 

  46. Kolls JK, Lei D, Odom G, et al. (1996) Use of transient CD4 lymphocyte depletion to prolong transgene expression of E1-deleted adenoviral vectors. Hum. Gene Ther. 7: 489–497.

    Article  CAS  Google Scholar 

  47. Stein CS, Pemberton JL, Vanrooijen N, Davidson BL. (1998) Effects of macrophage depletion and anti-CD40 ligand on transgene expression and redosing with recombinant adenovirus. Gene Therapy 5: 431–439.

    Article  CAS  Google Scholar 

  48. Kass-Eisler A, Leinwand L, Gall J, Bloom B, Falck-Pedersen E. (1996) Circumventing the immune response to adenovirus-mediated gene therapy. Gene Therapy 3: 154–162.

    PubMed  CAS  Google Scholar 

  49. Mack CA, Song W-R, Carpenter H, et al. (1997) Circumvention of anti-adenovirus neutralizing immunity by administration of an adenoviral vector af an alternate serotype. Hum. Gene Ther. 8: 99–109.

    Article  CAS  Google Scholar 

  50. Mastrangeli A, Harvey BG, Yao J, et al. (1996) Sero-switch adenovirus-mediated in vivo gene transfer-circumvention of anti-adenovirus humoral immune defenses against repeat adenovirus vector administration by changing the adenovirus serotype. Hum. Gene Ther. 7: 79–87.

    Article  CAS  Google Scholar 

  51. Walter J, You Q, Hagstrom JN, Sands M, High KA. (1996) Successful expression of human factor IX following repeat administration of an adenoviral vector in mice. Proc. Natl. Acad. Sci. U.S.A. 93: 3056–3061.

    Article  CAS  Google Scholar 

  52. De Matteo RP, Raper SE, Ahn M, et al. (1995) Gene transfer to the thymus. A means of abrogating the immune response to recombinant adenovirus. Ann. Surg. 222: 229–239.

    Article  Google Scholar 

  53. Kitamura D, Roes J, Kuhn R, Rajewsky K. (1991) A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 350: 423–426.

    Article  CAS  Google Scholar 

  54. Epstein MM, DiRosa F, Jankovic D, Sher A, Matzinger P. (1995) Successful T cell priming in B cell-deficient mice. J. Exp. Med. 182: 915–922.

    Article  CAS  Google Scholar 

  55. McGrory WJ, Bautista DS, Graham FL. (1988) A simple technique for the rescue of early region 1 mutations into infectious human adenovirus type 5. Virology 163: 614–617.

    Article  CAS  Google Scholar 

  56. Graham FL, Prevec L (1991) Manipulation of adenovirus vectors. In: Murray EJ (ed.) Methods in Molecular Biology: Gene Transfer and Expression Protocols. The Humana Press, Inc., Clifton, N.J, pp. 109–128.

    Chapter  Google Scholar 

  57. Nyberg-Hoffman C, Shabram P, Li W, Giroux D, Aguilar-Cordova E. (1997) Sensitivity and reproducibility in adenoviral infectious titer determination. Nat. Med. 3: 808–811.

    Article  CAS  Google Scholar 

  58. Chen L, Anton M, Graham F. (1996) Production and characterization of human 293 cell lines expressing the site-specific recombinase Cre. Somatic Cell Mol. Genet. 22: 477–488.

    Article  CAS  Google Scholar 

  59. Parks RJ, Chen L, Anton M, et al. (1996) A helper-dependent adenovirus vector system: Removal of helper virus by Cre-mediated excision of the viral packaging signal. Proc. Natl. Acad. Sci. U.S.A. 93: 13565–13570.

    Article  CAS  Google Scholar 

  60. Mittereder N, March KL, Trapnell BC. (1996) Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy. J. Virol. 70: 7498–7509.

    PubMed  PubMed Central  CAS  Google Scholar 

  61. Mombaerts P, Iacomini J, Johnson RS, et al. (1992) Rag-1-deficient mice have no mature B and T lymphocytes. Cell 68: 869–877.

    Article  CAS  Google Scholar 

  62. Kay MA, Graham F, Leland F, Woo SLC. (1995) Therapeutic serum concentrations of human alpha-1-antitrypsin after adenoviral-mediated gene transfer into mouse hepatocytes. Hepatology 21: 815–819.

    PubMed  CAS  Google Scholar 

  63. MacGregor GR, Mogg AE, Burke JF, Caskey CT. (1987) Histochemical staining of clonal mammalian cell lines expressing E. coli β-galactosidase indicate heterogeneous expression of the bacterial gene. Somatic Cell Mol. Genet. 13: 253–365.

    Article  CAS  Google Scholar 

  64. Duchrow M, Schluter C, Key G, Kubbutat, M. H. G., et al. (1995) Cell proliferation-associated nuclear antigen defined by antibody Ki-67: a new kind of cell cycle-maintaining proteins. Arch. Immunol. Ther. Exp. 43: 117–121.

    CAS  Google Scholar 

  65. Gerdes J, Schwab U, Lemke H, Stein H. (1983) Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int. J. Can. 31: 13–20.

    Article  CAS  Google Scholar 

  66. Guo ZS, Wang L-H, Eisensmith RC, Woo SLC. (1996) Evaluation of promoter strength for hepatic gene expression in vivo following adenovirus-mediated gene transfer. Gene Therapy 3: 802–810.

    PubMed  CAS  Google Scholar 

  67. Li S, Holdsworth SR, Tipping PG. (1997) Antibody independent crescentic glomerulonephritis in m chain deficient mice. Kidney Int. 51: 672–678.

    Article  CAS  Google Scholar 

  68. Asano MS, Ahmed R. (1983) CD8 T cell memory in B cell-deficient mice. J. Exp. Med. 183: 2165–2174.

    Article  Google Scholar 

  69. Jonic S, Pavic I, Polic B, et al. (1994) Anitbodies are not essential for the resolution of primary cytomegalovirus infection but limit dissemination of recurrent virus. J. Exp. Med. 179: 1713–1717.

    Article  Google Scholar 

  70. Brundler MA, Aichele P, Bachmann M, et al. (1996) Immunity to viruses in B cell-deficient mice: influence of antibodies on virus persistence and on T cell memory. Eur. J. Immunol. 26: 2257–2262.

    Article  CAS  Google Scholar 

  71. Williams DM, Grubbs BG, Pack E, Kelly K, Rank RG. (1997) Humoral and cellular immunity in secondary infection due to muring Chlamydia trachomatis. Infect. Immun. 65: 2876–2882.

    PubMed  CAS  Google Scholar 

  72. Su H. (1997) Chlamydia trachomatis genital tract infection of antibody-deficient gene knockout mice. Infect. Immun. 65: 1993–1999.

    PubMed  PubMed Central  CAS  Google Scholar 

  73. Benda B, Karlsson-Parra A, Ridderstad A, Korsgren O. (1996) Xenograft rejection of porcine islet-like cell clusters in immunoglobulin or Fc-receptor gamma-deficient mice. Transplantation 62: 1207–1211.

    Article  CAS  Google Scholar 

  74. Wadsworth SC, Zhou H, Smith AE, Kaplan JM. (1997) Adenovirus vector-infected cells can escape adenovirus antigen-specific cytotoxic T-lymphocyte killing in vivo. J. Virol. 71: 5189–5196.

    PubMed  PubMed Central  CAS  Google Scholar 

  75. Kozarsky KF, Jooss K, Donahee M, Strauss JFI, Wilson JM. (1996) Effective treatment of familial hypercholesterolaemia in the mouse model using adenovirus-mediated transfer of the VLDL receptor gene. Nat. Genet. 13: 54–62.

    Article  CAS  Google Scholar 

  76. Wersto RP, Rosenthal ER, Seth PK, Eissa NT, Donahue RE. (1998) Recombinant, replication-defective adenovirus gene transfer vectors induce cell cycle dysregulation and inappropriate expression of cyclin proteins. J. Virol. 72: 9491–9502.

    PubMed  PubMed Central  CAS  Google Scholar 

  77. Barr D, Tubb J, Ferguson D, et al. (1995) Strain related variations in adenovirally mediated transgene expression from mouse hepatocytes in vivo: comparisons between immunocompetent and immunodeficient inbred strains. Gene Therapy 2: 151–155.

    PubMed  CAS  Google Scholar 

  78. Bett AJ, Haddara W, Prevec L, Graham FL. (1994) An efficient and flexible system for construction of adenovirus vectors with insertions or deletions in early regions 1 and 3. Proc. Natl. Acad. Sci. U.S.A. 91: 8802–8806.

    Article  CAS  Google Scholar 

  79. Niwa H, Yamamura K, Mizyzaki J. (1991) Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108: 193–200.

    Article  CAS  Google Scholar 

  80. Kiwaki K, Matsuda I. (1996) Gene therapy for ornithine transcarbamylase deficiency. Acta Paediatrica Japonica 38: 189–192.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Yufen Wang and Rizwan Velji for excellent technical assistance, Janet Quinones for performing the sectioning and histochemical stains, and the Baylor College of Medicine Gene Vector Production Core Laboratory, especially Dr. Estuardo Aguilar-Cordova and Cassandra Nyberg-Hoffman, for production of the first-generation vectors used in these experiments. This work was supported by grants from the Cystic Fibrosis Foundation (S882, F806, and F984), the NIH (HL51754). F. G. and R. P. are also supported by the Natural Sciences and Engineering Research Council, the Medical Research Council, and the National Cancer Institute of Canada. N. M. is a recipeint of a fellowship from the Ministerio de Educacion y Cultura (Spain).

Author information

Author notes

  1. Wanda K. O’Neal (Ph.D.), Robin J. Parks & Frank L. Graham

    Present address: Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, 7011 Thurston-Bowles Building, CB# 7248, Chapel Hill, North Carolina, 27599-7248, USA

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Wanda K. O’Neal (Ph.D.), Heshan Zhou, Núria Morral, Stefan Kochanek & Arthur L. Beaudet

  2. Department of Pathology, Baylor College of Medicine, Houston, TX, USA

    Claire Langston

  3. Departments of Biology and Pathology, McMaster University, Hamilton, Ontario, Canada

    Wanda K. O’Neal (Ph.D.), Heshan Zhou, Núria Morral, Claire Langston, Robin J. Parks, Frank L. Graham, Stefan Kochanek & Arthur L. Beaudet

Authors
  1. Wanda K. O’Neal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Heshan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Núria Morral
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claire Langston
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robin J. Parks
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Frank L. Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stefan Kochanek
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Arthur L. Beaudet
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wanda K. O’Neal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

O’Neal, W.K., Zhou, H., Morral, N. et al. Toxicity Associated with Repeated Administration of First-Generation Adenovirus Vectors Does Not Occur with a Helper-Dependent Vector. Mol Med 6, 179–195 (2000). https://doi.org/10.1007/BF03402113

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03402113

Keywords

Search

Navigation