Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

Adenovirus serotype 35 vector-mediated transduction following direct administration into organs of nonhuman primates

Gene Therapy volume 16, pages 297–302 (2009)Cite this article

Abstract

Adenovirus (Ad) serotype 35 (Ad35) vectors have attracted remarkable attention as alternatives to conventional Ad serotype 5 (Ad5) vectors. In a previous study, we showed that intravenously administered Ad35 vectors exhibited a safer profile than Ad5 vectors in cynomolgus monkeys, which ubiquitously express CD46, an Ad35 receptor, in a pattern similar to that in humans. However, the Ad35 vectors poorly transduced the organs. In this study, we examined the transduction properties of Ad35 vectors after local administration into organs of cynomolgus monkeys. The vectors transduced different types of cells depending on the organ. Hepatocytes and microglia were mainly transduced after the vectors were injected into the liver and cerebrum, respectively. Injection of the vectors into the femoral muscle resulted in the transduction of cells that appeared to be fibroblasts and/or macrophages. Conjunctival epithelial cells showed transgene expression following infusion into the vitreous body of the eyeball. Transgene expression was limited to areas around the injection points in most of the organs. In contrast, Ad35 vector-mediated transgene expression was not detected in any of the organs not injected with Ad35 vectors. These results suggest that Ad35 vectors are suitable for gene delivery by direct administration to organs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Havenga MJ, Lemckert AA, Ophorst OJ, van Meijer M, Germeraad WT, Grimbergen J et al. Exploiting the natural diversity in adenovirus tropism for therapy and prevention of disease. J Virol 2002; 76: 4612–4620.

    Article  CAS  Google Scholar 

  2. De Jong JC, Wermenbol AG, Verweij-Uijterwaal MW, Slaterus KW, Wertheim-Van Dillen P, Van Doornum GJ et al. Adenoviruses from human immunodeficiency virus-infected individuals, including two strains that represent new candidate serotypes Ad50 and Ad51 of species B1 and D, respectively. J Clin Microbiol 1999; 37: 3940–3945.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lemckert AA, Sumida SM, Holterman L, Vogels R, Truitt DM, Lynch DM et al. Immunogenicity of heterologous prime-boost regimens involving recombinant adenovirus serotype 11 (Ad11) and Ad35 vaccine vectors in the presence of anti-ad5 immunity. J Virol 2005; 79: 9694–9701.

    Article  CAS  Google Scholar 

  4. Nanda A, Lynch DM, Goudsmit J, Lemckert AA, Ewald BA, Sumida SM et al. Immunogenicity of recombinant fiber-chimeric adenovirus serotype 35 vector-based vaccines in mice and rhesus monkeys. J Virol 2005; 79: 14161–14168.

    Article  CAS  Google Scholar 

  5. Mizuguchi H, Hayakawa T . Enhanced antitumor effect and reduced vector dissemination with fiber-modified adenovirus vectors expressing herpes simplex virus thymidine kinase. Cancer Gene Ther 2002; 9: 236–242.

    Article  CAS  Google Scholar 

  6. Okada Y, Okada N, Mizuguchi H, Hayakawa T, Mayumi T, Mizuno N . An investigation of adverse effects caused by the injection of high-dose TNFalpha-expressing adenovirus vector into established murine melanoma. Gene Therapy 2003; 10: 700–705.

    Article  CAS  Google Scholar 

  7. Suzuki T, Sakurai F, Nakamura S, Kouyama E, Kawabata K, Kondoh M et al. miR-122a-regulated expression of a suicide gene prevents hepatotoxicity without disturbing the antitumor effects in suicide gene therapy. Mol Ther 2008, (in press).

  8. Sakurai F, Mizuguchi H, Hayakawa T . Efficient gene transfer into human CD34+ cells by an adenovirus type 35 vector. Gene Therapy 2003; 10: 1041–1048.

    Article  CAS  Google Scholar 

  9. Vogels R, Zuijdgeest D, van Rijnsoever R, Hartkoorn E, Damen I, de Bethune MP et al. Replication-deficient human adenovirus type 35 vectors for gene transfer and vaccination: efficient human cell infection and bypass of preexisting adenovirus immunity. J Virol 2003; 77: 8263–8271.

    Article  CAS  Google Scholar 

  10. Gao W, Robbins PD, Gambotto A . Human adenovirus type 35: nucleotide sequence and vector development. Gene Therapy 2003; 10: 1941–1949.

    Article  CAS  Google Scholar 

  11. Seshidhar Reddy P, Ganesh S, Limbach MP, Brann T, Pinkstaff A, Kaloss M et al. Development of adenovirus serotype 35 as a gene transfer vector. Virology 2003; 311: 384–393.

    Article  CAS  Google Scholar 

  12. Sakurai F, Mizuguchi H, Yamaguchi T, Hayakawa T . Characterization of in vitro and in vivo gene transfer properties of adenovirus serotype 35 vector. Mol Ther 2003; 8: 813–821.

    Article  CAS  Google Scholar 

  13. Sakurai F, Kawabata K, Koizumi N, Inoue N, Okabe M, Yamaguchi T et al. Adenovirus serotype 35 vector-mediated transduction into human CD46-transgenic mice. Gene Therapy 2006; 13: 1118–1126.

    Article  CAS  Google Scholar 

  14. Verhaagh S, de Jong E, Goudsmit J, Lecollinet S, Gillissen G, de Vries M et al. Human CD46-transgenic mice in studies involving replication-incompetent adenoviral type 35 vectors. J Gen Virol 2006; 87: 255–265.

    Article  CAS  Google Scholar 

  15. Sakurai F, Nakamura S, Akitomo K, Shibata H, Terao K, Kawabata K et al. Transduction properties of adenovirus serotype 35 vectors after intravenous administration into nonhuman primates. Mol Ther 2008; 16: 726–733.

    Article  CAS  Google Scholar 

  16. Sakai M, Nishikawa M, Thanaketpaisarn O, Yamashita F, Hashida M . Hepatocyte-targeted gene transfer by combination of vascularly delivered plasmid DNA and in vivo electroporation. Gene Therapy 2005; 12: 607–616.

    Article  CAS  Google Scholar 

  17. Crettaz J, Berraondo P, Mauleon I, Ochoa L, Shankar V, Barajas M et al. Intrahepatic injection of adenovirus reduces inflammation and increases gene transfer and therapeutic effect in mice. Hepatology 2006; 44: 623–632.

    Article  CAS  Google Scholar 

  18. Bora NS, Gobleman CL, Atkinson JP, Pepose JS, Kaplan HJ . Differential expression of the complement regulatory proteins in the human eye. Invest Ophthalmol Vis Sci 1993; 34: 3579–3584.

    CAS  PubMed  Google Scholar 

  19. Thirion C, Lochmuller H, Ruzsics Z, Boelhauve M, Konig C, Thedieck C et al. Adenovirus vectors based on human adenovirus type 19a have high potential for human muscle-directed gene therapy. Hum Gene Ther 2006; 17: 193–205.

    Article  CAS  Google Scholar 

  20. Danko I, Williams P, Herweijer H, Zhang G, Latendresse JS, Bock I et al. High expression of naked plasmid DNA in muscles of young rodents. Hum Mol Genet 1997; 6: 1435–1443.

    Article  CAS  Google Scholar 

  21. Wang AY, Peng PD, Ehrhardt A, Storm TA, Kay MA . Comparison of adenoviral and adeno-associated viral vectors for pancreatic gene delivery in vivo. Hum Gene Ther 2004; 15: 405–413.

    Article  CAS  Google Scholar 

  22. Hierholzer JC . Adenoviruses in the immunocompromised host. Clin Microbiol Rev 1992; 5: 262–274.

    Article  CAS  Google Scholar 

  23. Sakurai F, Nakamura S, Akitomo K, Shibata H, Terao K, Hayakawa T et al. Transduction properties of adenovirus serotype 35 vectors after intravenous administration in nonhuman primates. Mol Ther 2008; 16: 726–733.

    Article  CAS  Google Scholar 

  24. Shirakawa T, Terao S, Hinata N, Tanaka K, Takenaka A, Hara I et al. Long-term outcome of phase I/II clinical trial of Ad-OC-TK/VAL gene therapy for hormone-refractory metastatic prostate cancer. Hum Gene Ther 2007; 18: 1225–1232.

    Article  CAS  Google Scholar 

  25. Shimada H, Matsubara H, Shiratori T, Shimizu T, Miyazaki S, Okazumi S et al. Phase I/II adenoviral p53 gene therapy for chemoradiation resistant advanced esophageal squamous cell carcinoma. Cancer Sci 2006; 97: 554–561.

    Article  CAS  Google Scholar 

  26. Tong AW, Nemunaitis J, Su D, Zhang Y, Cunningham C, Senzer N et al. Intratumoral injection of INGN 241, a nonreplicating adenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24): biologic outcome in advanced cancer patients. Mol Ther 2005; 11: 160–172.

    Article  CAS  Google Scholar 

  27. Catanzaro AT, Koup RA, Roederer M, Bailer RT, Enama ME, Moodie Z et al. Phase 1 safety and immunogenicity evaluation of a multiclade HIV-1 candidate vaccine delivered by a replication-defective recombinant adenovirus vector. J Infect Dis 2006; 194: 1638–1649.

    Article  CAS  Google Scholar 

  28. Rosenberg SA, Zhai Y, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM et al. Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens. J Natl Cancer Inst 1998; 90: 1894–1900.

    Article  CAS  Google Scholar 

  29. Stewart DJ, Hilton JD, Arnold JM, Gregoire J, Rivard A, Archer SL et al. Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF(121) (AdVEGF121) versus maximum medical treatment. Gene Therapy 2006; 13: 1503–1511.

    Article  CAS  Google Scholar 

  30. Rosengart TK, Lee LY, Patel SR, Kligfield PD, Okin PM, Hackett NR et al. Six-month assessment of a phase I trial of angiogenic gene therapy for the treatment of coronary artery disease using direct intramyocardial administration of an adenovirus vector expressing the VEGF121 cDNA. Ann Surg 1999; 230: 466–470; discussion 470–472.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Fumiko Ono and Chieko Ohno (The Corporation for Production and Research of Laboratory Primates, Ibaraki, Japan) for their help. This study was supported by grants from the Ministry of Health, Labour, and Welfare of Japan and by a Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan.

Author information

Author notes

  1. S-i Nakamura

    Present address: 7Current address: Research Center of Animal Life Science, Shiga University of Medical Science, Otsu City, Shiga, Japan.,

Authors and Affiliations

  1. Laboratory of Gene Transfer and Regulation, National Institute of Biomedical Innovation, Ibaraki City, Osaka, Japan

    F Sakurai, K Akitomo, K Kawabata & H Mizuguchi

  2. Tsukuba Primates Research Center, National Institute of Biomedical Innovation, Tsukuba City, Ibaraki, Japan

    S-i Nakamura, H Shibata & K Terao

  3. The Corporation for Production and Research of Laboratory Primates, Tsukuba City, Ibaraki, Japan

    S-i Nakamura

  4. Pharmaceuticals and Medical Devices Agency, Chiyoda-Ku, Tokyo, Japan

    T Hayakawa

  5. Pharmaceutical Research and Technology Institute, Kinki University, Osaka, Japan

    T Hayakawa

  6. Graduate School of Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan

    H Mizuguchi

Authors
  1. F Sakurai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S-i Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Akitomo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Shibata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Terao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Kawabata
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Hayakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H Mizuguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Mizuguchi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sakurai, F., Nakamura, Si., Akitomo, K. et al. Adenovirus serotype 35 vector-mediated transduction following direct administration into organs of nonhuman primates. Gene Ther 16, 297–302 (2009). https://doi.org/10.1038/gt.2008.154

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2008.154

Keywords

This article is cited by

Search

Advanced search

Quick links