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.

  • Research Article
  • Published:

Localized adenovirus gene delivery using antiviral IgG complexation

Gene Therapy volume 8, pages 659–667 (2001)Cite this article

Abstract

Gene therapy with viral vectors has progressed to clinical trials. However, the localization of viral vector delivery to diseased target sites remains a challenge. We tested the hypothesis that an adenoviral vector could be successfully delivered by complexation with a specific antibody that is bound to a biodegradable matrix designed for achieving localized gene transduction. We report the first successful delivery system based upon antibody immobilization of virions in a type I collagen-avidin gel using a polyclonal biotinylated IgG specific for the adenovirus hexon. In vitro stability studies demonstrated retention of viral vector activity with antibody-complexed adenovirus collagen gel preparations, in comparison to loss of vector activity from collagen gels prepared with nonspecific biotinylated IgG. Cell culture investigations using this antibody-controlled release system for adenoviral vector transduction of rat aortic smooth muscle cells (A10) demonstrated a significantly more localized reporter expression (β-galactosidase) compared with non-antibody-complexed controls. Herpes simplex thymidine kinase (HSVtk) adenoviral vectors were immobilized on avidin-collagen gels via this antibody-complexation approach, and ganciclovir was added to rat smooth muscle cells (A10) in culture with the gels. With complexed HSVtk adenovirus, only cells either in contact with the virus-containing gel or within 50 μm were killed. By comparison, at the same adenovirus and ganciclovir dose, non-antibody-complexed HSVtk adenoviral delivery with ganciclovir resulted in the death of virtually all cells. Myocardial gene transfer studies in pigs demonstrated significantly more efficient right ventricular adenoviral GFP expression with anti-hexon antibody-complexed matrix injections, compared with direct vector injections. Thus, our results show that matrix formulations based on antibody-complexation delivery of adenovirus resulted in site-specific localization of transgene expression that enhances the efficiency of therapeutic vector strategies and provides a potent means for localization, to avoid distal side-effects. This approach has therapeutic potential as an implantable preparation that through the means of antibody-complexation, can localize and optimize viral vector gene therapy.

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
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Nguyen DM et al. Gene therapy for lung cancer: enhancement of tumor suppression by a combination of sequential systemic cisplatin and adenovirus-mediated p53 gene transfer J Thorac Cardiovasc Surg 1996 112: 1372–1377

    Article  CAS  Google Scholar 

  2. Rosenecker J et al. Adenovirus infection in cystic fibrosis patients: implications for the use of adenoviral vectors for gene transfer Infection 1996 24: 5–8

    Article  CAS  Google Scholar 

  3. Raper SE et al. Developing adenoviral-mediated in vivo gene therapy for ornithine transcarbamylase deficiency J Inherit Metab Dis 1998 21 (Suppl. 1): 119–137

    Article  CAS  Google Scholar 

  4. Sterman DH, Kaiser LR, Albelda SM . Gene therapy for malignant pleural mesothelioma Hematol Oncol Clin North Am 1998 12: 553–568

    Article  CAS  Google Scholar 

  5. Knoell DL, Yiu IM . Human gene therapy for heriditary diseases: a review of trials Am J Health-Syst Pharm 1998 55: 899–904

    CAS  PubMed  Google Scholar 

  6. Herman JR et al. In situ gene therapy for adenocarcinoma of the prostate: a phase I clinical trial Hum Gene Ther 1999 10: 1239–1249

    Article  CAS  Google Scholar 

  7. Habib NA, Hodgson HJ, Lemoine N, Pignatelli M . A phase I/II study of hepatic artery infusion with wtp53-CMV-Ad in metastatic malignant liver tumors Hum Gene Ther 1999 10: 2019–2034

    Article  CAS  Google Scholar 

  8. Stewart AK et al. Adenovector-mediated gene delivery of interleukin-2 in metastatic breast cancer and melanoma: results of a phase 1 clinical trial Gene Therapy 1999 6: 350–363

    Article  CAS  Google Scholar 

  9. Langer R . New methods of drug delivery Science 1990 249: 1527–1533

    Article  CAS  Google Scholar 

  10. Langer R . Drug delivery and targeting Nature 1998 392: 5–10

    CAS  Google Scholar 

  11. Bartus RT, Tracy MA, Emerich DF, Zale SE . Sustained delivery of proteins for novel therapeutic agents Science 1998 281: 1161–1162

    Article  CAS  Google Scholar 

  12. Edelman ER, Nugent MA, Karnovsky MJ . Perivascular and intravenous administration of basic fibroblast growth factor: vascular and solid organ deposition Proc Natl Acad Sci USA 1993 90: 1513–1517

    Article  CAS  Google Scholar 

  13. Langer R, Folkman J . Polymers for the sustained release of proteins and other macromolecules Nature 1976 263: 797–800

    Article  CAS  Google Scholar 

  14. Petka WA et al. Reversible hydrogels from self-assembling artificial proteins Science 1998 281: 389–392

    Article  CAS  Google Scholar 

  15. Spitz IM, Chertin B, Lindenberg T, Farkas A . Long-acting gonadatropin-releasing hormone implant to maintain medical castration for two years in men with prostate cancer New Engl J Med 1999 340: 1439

    Article  CAS  Google Scholar 

  16. Simons M et al. Antisense c-myb oligonucleotides inhibit intimal arterial smooth muscle cell accumulation in vivo Nature 1992 359: 67–70

    Article  CAS  Google Scholar 

  17. Simons M, Edelman ER, Rosenberg RD . Antisense proliferating cell nuclear antigen oligonucleotides inhibit intimal hyperplasia in a rat carotide artery injury model J Clin Invest 1994 93: 2351–2356

    Article  CAS  Google Scholar 

  18. Sirois MG, Simons M, Edelman ER . Antisense oligonucleotide inhibition of PDGFR-beta receptor subunit expression directs suppression of intimal thickening Circulation 1997 95: 669–676

    Article  CAS  Google Scholar 

  19. Mann MJ et al. Pressure-mediated aligonucleotide transfection of rat and human cardiovascular tissues Proc Natl Acad Sci USA 1999 96: 6411–6416

    Article  CAS  Google Scholar 

  20. Villa AE et al. Effects of antisense c-myb oligonucleotides on vascular smooth muscle cell proliferation and response to vessel wall injury Circ Res 1995 76: 505–513

    Article  CAS  Google Scholar 

  21. Bonadio J, Smiley E, Patil P, Goldstein S . Localized direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration Nat Med 1999 5: 753–759

    Article  CAS  Google Scholar 

  22. Labhasetwar V et al. A DNA controlled-release coating for gene transfer: transfection in skeletal and cardiac muscle J Pharm Sci 1998 87: 1347–1350

    Article  CAS  Google Scholar 

  23. Labhasetwar V et al. Gene transfection using biodegradable nanospheres: results in tissue culture and a rat osteotomy model. Coll Surf B Biointerf 1999 16: 281–290

    Article  CAS  Google Scholar 

  24. Roy K, Mao HQ, Huang SK, Leong KW . Oral gene delivery with chitosan–DNA nanoparticles generates immunologic protection in a murine model of peanut allergy Nat Med 1999 5: 387–391

    Article  CAS  Google Scholar 

  25. Shea LD, Smiley E, Bonadio J, Mooney DJ . DNA delivery from polymer matrices for tissue engineering Nat Biotechnol 1999 17: 551–554

    Article  CAS  Google Scholar 

  26. Beer SJ et al. Poly (lactic-glycolic) acid copolymer encapsulation of recombinant adenovirus reduces immunogenicity in vivo Gene Therapy 1998 5: 740–746

    Article  CAS  Google Scholar 

  27. Kalyanasundaram S et al. Coacervate microspheres as carriers of recombinant adenoviruses Cancer Gene Ther 1999 6: 107–112

    Article  CAS  Google Scholar 

  28. Sintov A, Ankol S, Levy DP, Rubinstein A . Enzymatic cleavage of disaccharide side groups in insoluble synthetic polymers: a new method for specific delivery of drugs to the colon Biomaterials 1993 14: 483–490

    Article  CAS  Google Scholar 

  29. van Dijk-Wolthius WN et al. A versatile method for the conjugation of proteins and peptides to poly[2-(dimethylamino)ethyl methacrylate] Bioconjug Chem 1999 10: 687–692

    Article  Google Scholar 

  30. Song C et al. Antibody tethered adenovirus for stent-based vector delivery in pig coronaries Circulation 2000 102: (Suppl. II) 566

    Google Scholar 

  31. Degreve B, De Clercq E, Balzarini J . Bystander effect of purine nucleoside analogues in HSV-1 tk suicide gene therapy is superior to that of pyrimidine nucleoside analogues Gene Therapy 1999 6: 162–170

    Article  CAS  Google Scholar 

  32. Kuriyama S et al. Cancer gene therapy with HSV-tk/GCV system depends on T-cell-mediated immune responses and causes apoptotic death of tumor cells in vivo Int J Cancer 1999 83: 374–380

    Article  CAS  Google Scholar 

  33. Guzman RJ et al. In vivo suppression of injury-induced vascular smooth muscle cell accumulation using adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene Proc Natl Acad Sci USA 1994 91: 10732–10736

    Article  CAS  Google Scholar 

  34. Chang MW et al. Adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene inhibits vascular smooth muscle cell proliferation and neointima formation following balloon angioplasty of the rat carotid artery Mol Med 1995 1: 172–181

    Article  CAS  Google Scholar 

  35. Chandler LA et al. FGF2-targeted adenovirus encoding platelet derived growth factor-B enhances de noco tissue formation Mol Ther 2000 2: 153–160

    Article  CAS  Google Scholar 

  36. Kohler K, Veide A . Uses of fusions of beta-galactosidase and peptides to proteins Meth Enzymol 1994 228: 627–640

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Ms Ginger Nicholson for her manuscript preparation efforts. This research was supported in part by a grant from the National Institutes of Health (HL 41663), a grant from the Cystic Fibrosis Foundation, and by The William J Rashkind Endowment of The Children's Hospital of Philadelphia.

Author information

Authors and Affiliations

  1. Division of Cardiology, Children's Hospital of Philadelphia, PA, USA

    R J Levy, C Song, S Tallapragada, S DeFelice, J Travis Hinson, N Vyavahare, J Connolly, K Ryan & Q Li

Authors
  1. R J Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Tallapragada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S DeFelice
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Travis Hinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N Vyavahare
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Connolly
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Ryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Q Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Levy, R., Song, C., Tallapragada, S. et al. Localized adenovirus gene delivery using antiviral IgG complexation. Gene Ther 8, 659–667 (2001). https://doi.org/10.1038/sj.gt.3301452

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301452

Keywords

This article is cited by

Search

Advanced search

Quick links