Cell Biochemistry and Biophysics

, Volume 48, Issue 2–3, pp 183–190 | Cite as

The status of gene vectors for the treatment of diabetes

  • John A. ZaiaEmail author
Original Paper


Diabetes mellitus type 1 (DM1) represents one of the most obvious targets for successful treatment by gene transfer. The disease provides targets and methods for therapy that include suppression of autoimmunity, restoration of insulin responsiveness, functional replacement of pancreatic islets, and correction of vascular and nerve damage associated with prolonged hyperglycemia. The pathogenesis of DM1 is well understood and gene sequences are known that would support these various approaches for genetic intervention. However, a key limitation at present is the availability of efficient and reliable methods for delivery and sustained expression of the transferred DNA. Most genetic vectors are derived from viruses, and recent improvements in adenovirus-derived, lentivirus-derived, and adeno-associated virus-derived vectors suggest that these will have successful application to diabetes in the future.


Vectors Lentivirus Adenovirus Adeno-assoicated virus Retrovirus Gene therapy 


  1. 1.
    Marti, G. E., Bauer, S., Puri, R. K., & Noguchi, P. D. (1994). Regulatory review of cellular and gene therapies: An overview of the process. Transfusion Science, 15, 323–329.PubMedCrossRefGoogle Scholar
  2. 2.
    Yechoor, V., & Chan, L. (2005). Gene therapy progress and prospects: Gene therapy for diabetes mellitus. Gene Therapy, 12, 101–107.PubMedCrossRefGoogle Scholar
  3. 3.
    Carter, J. D., Ellett, J. D., Chen, M., Smith, K. M., Fialkow, L. B., McDuffie, M. J., Tung, K. S., Nadler, J. L., & Yang, Z. (2005). Viral IL-10-mediated immune regulation in pancreatic islet transplantation. Molecular Therapy, 12, 360–368.PubMedCrossRefGoogle Scholar
  4. 4.
    Luo, X., Yang, H., Kim, I. S., Saint-Hilaire, F., Thomas, D. A., De, B. P., Ozkaynak, E., Muthukumar, T., Hancock, W. W., Crystal, R. G., & Suthanthiran, M. (2005). Systemic transforming growth factor-beta1 gene therapy induces Foxp3+ regulatory cells, restores self-tolerance, and facilitates regeneration of beta cell function in overtly diabetic nonobese diabetic mice. Transplantation, 79, 1091–1096.PubMedCrossRefGoogle Scholar
  5. 5.
    Ou, D., Wang, X., Metzgen, D. L., James, R. F., Pozzilli, P., Plesner, A., Korneluk, R. G., Verchere, C. B., & Tingle, A. J. (2005). Synergistic inhibition of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human pancreatic beta cells by Bcl-2 and X-linked inhibitor of apoptosis. Human Immunology, 66, 274–284.PubMedCrossRefGoogle Scholar
  6. 6.
    Han, G., Li, Y., Wang, J., Wang, R., Chen, G., Song, L., Xu, R., Yu, M., Wu, X., Qian, J., & Shen, B. (2005). Active tolerance induction and prevention of autoimmune diabetes by immunogene therapy using recombinant adenoassociated virus expressing glutamic acid decarboxylase 65 peptide GAD(500–585). Journal of Immunology, 174, 4516–4524.Google Scholar
  7. 7.
    Alam, T., & Sollinger, H. W. (2002). Glucose-regulated insulin production in hepatocytes. Transplantation, 74, 1781–1787.PubMedCrossRefGoogle Scholar
  8. 8.
    Ber, I., Shternhall, K., Perl, S., Ohanuna, Z., Goldberg, I., Barshack, I., Benvenisti-Zarum, L., Meivar-Levy, I., & Ferber, S. (2003). Functional, persistent, and extended liver to pancreas transdifferentiation. The Journal of Biological Chemistry, 278, 31950–31957.PubMedCrossRefGoogle Scholar
  9. 9.
    Sapir, T., Shternhall, K., Meivar-Levy, I., Blumenfeld, T., Cohen, H., Skutelsky, E., Eventov-Friedman, S., Barshack, I., Goldberg, I., Pri-Chen, S., Ben-Dor, L., Polak-Charcon, S., Karasik, A., Shimon, I., Mor, E., & Ferber, S. (2005). Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells. Proceedings of the National Academy of Sciences of the United States of America, 102, 7964–7969.PubMedCrossRefGoogle Scholar
  10. 10.
    Kobinger, G. P., Deng, S., Louboutin, J. P., Vatamaniuk, M., Rivera, V. M., Kian, M. M., Markmann, J. F., Clackson, T., Raper, S. E., Matschinsky, F., & Wilson, J. M. (2005). Pharmacologically regulated regeneration of functional human pancreatic islets. Molecular Therapy, 11, 105–111.PubMedCrossRefGoogle Scholar
  11. 11.
    Lebherz, C., Maguire, A. M., Auricchio, A., Tang, W., Aleman, T. S., Wei, Z., Grant, R., Cideciyan, A. V., Jacobson, S. G., Wilson, J. M., & Bennett, J. (2005). Nonhuman primate models for diabetic ocular neovascularization using AAV2-mediated overexpression of vascular endothelial growth factor. Diabetes, 54, 1141–1149.PubMedCrossRefGoogle Scholar
  12. 12.
    Isner, J. M., Ropper, A., & Hirst, K. (2001). VEGF gene transfer for diabetic neuropathy. Human Gene Therapy, 12, 1593–1594.PubMedGoogle Scholar
  13. 13.
    Mohler, E. R. 3rd, Rajagopalan, S., Olin, J. W., Trachtenberg, J. D., Rasmussen, H., Pak, R., & Crystal, R. G. (2003). Adenoviral-mediated gene transfer of vascular endothelial growth factor in critical limb ischemia: Safety results from a phase I trial. Vascular Medicine, 8, 9–13.PubMedCrossRefGoogle Scholar
  14. 14.
    Diaz-Sandoval, L. J., & Losordo, D. W. (2003). Gene therapy for cardiovascular angiogenesis. Expert Opinion on Biological Therapy, 3, 599–616.PubMedCrossRefGoogle Scholar
  15. 15.
    Chan, L., Fujimiya, M., & Kojima, H. (2003). In vivo gene therapy for diabetes mellitus. Trends in Molecular Medicine, 9, 430–435.PubMedCrossRefGoogle Scholar
  16. 16.
    St George, J. A. (2003). Gene therapy progress and prospects: Adenoviral vectors. Gene Therapy, 10, 1135–1141.PubMedCrossRefGoogle Scholar
  17. 17.
    Danthinne, X. (2001). Simultaneous insertion of two expression cassettes into adenovirus vectors. Biotechniques, 30, 612–616 and 618–619.PubMedGoogle Scholar
  18. 18.
    Alba, R., Bosch, A., & Chillon, M. (2005). Gutless adenovirus: Last-generation adenovirus for gene therapy. Gene Therapy, 12, S18–S27.PubMedCrossRefGoogle Scholar
  19. 19.
    Raper, S. E., Yudoff, M., Chirmule, N., Gao, G. P., Nunes, F., Haskal, Z. J., Furth, E. E., Propert, K. J., Robinson, M. B., Magosin, S., Simoes, H., Speicher, L., Hughes, J., Tazelaar, J., Wivel, N. A., Wilson, J. M., & Batshaw, M. L. (2002). A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Human Gene Therapy, 13, 163–175.PubMedCrossRefGoogle Scholar
  20. 20.
    Raper, S. E., Chirmule, N., Lee, F. S., Wivel, N. A., Bagg, A., Gao, G. P., Wilson, J. M., & Batshaw, M. L. (2003). Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Molecular Genetics and Metabolism, 80, 148–158.PubMedCrossRefGoogle Scholar
  21. 21.
    Schnell, M. A.,Zhang, Y., Tazelaar, J., Gao, G. P., Yu, Q. C., Qian, R., Chen, S. J., Varnavski, A. N., LeClair, C., Raper, S. E., & Wilson, J. M. (2001). Activation of innate immunity in nonhuman primates following intraportal administration of adenoviral vectors. Molecular Therapy, 3, 708–722.PubMedCrossRefGoogle Scholar
  22. 22.
    Lozier, J. N., Csako, G., Mondor, T. H., Krizek, D. M., Metzger, M. E., Costello, R., Vostal, J. G., Rick, M. E., Donahue, R. E., & Morgan, R. A. (2002). Toxicity of a first-generation adenoviral vector in rhesus macaques. Human Gene Therapy, 13, 113–124.PubMedCrossRefGoogle Scholar
  23. 23.
    Morral, N., McEvoy, R., Dong, H., Meseck, M., Altomonte, J., Thung, S., & Woo, S. L. (2002). Adenovirus-mediated expression of glucokinase in the liver as an adjuvant treatment for type 1 diabetes. Human Gene Therapy, 13, 1561–1570.PubMedCrossRefGoogle Scholar
  24. 24.
    Nemerow, G. R. (2000). Adenoviral vectors–new insights. Trends in Microbiology, 8, 391–394.PubMedCrossRefGoogle Scholar
  25. 25.
    Ostapchuk, P., & Hearing, P. (2001). Pseudopackaging of adenovirus type 5 genomes into capsids containing the hexon proteins of adenovirus serotypes B, D, or E. Journal of Virology, 75, 45–51.PubMedCrossRefGoogle Scholar
  26. 26.
    van Beusechem, V. W., van Rijswijk, A. L., van Es, H. H., Haisma, H. J., Pinedo, H. M., & Gerritsen, W. R. (2000). Recombinant adenovirus vectors with knobless fibers for targeted gene transfer. Gene Therapy, 7, 1940–1946.PubMedCrossRefGoogle Scholar
  27. 27.
    Wickham, T. J. (2003). Ligand-directed targeting of genes to the site of disease. Nature Medicine, 9, 135–139.PubMedCrossRefGoogle Scholar
  28. 28.
    Israel, B. F., Pickles, R. J., Segal, D. M., Gerard, R. D., & Kenney, S. C. (2001). Enhancement of adenovirus vector entry into CD70-positive B-cell Lines by using a bispecific CD70-adenovirus fiber antibody. Journal of Virology, 75, 5215–5221.PubMedCrossRefGoogle Scholar
  29. 29.
    Levy, R. J., Song, C., Tallapragada, S., DeFelice, S., Hinson, J. T., Vyavahare, N., Connolly, J., Ryan, K., & Li, Q. (2001). Localized adenovirus gene delivery using antiviral IgG complexation. Gene Therapy, 8, 659–667.PubMedCrossRefGoogle Scholar
  30. 30.
    Nicklin, S. A., Von Seggern, D. J., Work, L. M., Pek, D. C., Dominiczak, A. F., Nemerow, G. R., & Baker, A. H. (2001). Ablating adenovirus type 5 fiber-CAR binding and HI loop insertion of the SIGYPLP peptide generate an endothelial cell-selective adenovirus. Molecular Therapy, 4, 534–542.PubMedCrossRefGoogle Scholar
  31. 31.
    Parker, A. L., Fisher, K. D., Oupicky, D., Read, M. L., Nicklin, S. A., Baker, A. H., & Seymour. L. W. (2005). Enhanced gene transfer activity of peptide-targeted gene-delivery vectors. Journal of Drug Targeting, 13, 39–51.PubMedCrossRefGoogle Scholar
  32. 32.
    Nicklin, S. A., & Baker, A. H. (2002). Tropism-modified adenoviral and adeno-associated viral vectors for gene therapy. Current Gene Therapy, 2, 273–293.PubMedCrossRefGoogle Scholar
  33. 33.
    Hacein-Bey-Abina, S., Von Kalle, C., Schmidt, M., McCormack, M. P., Wulffraat, N., Leboulch, P., Lim, A., Osborne, C. S., Pawliuk, R., Morillon, E., Sorensen, R., Forster, A., Fraser, P., Cohen, J. I., de Saint Basile, G., Alexander, I., Wintergerst, U., Frebourg, T., Aurias, A., Stoppa-Lyonnet, D., Romana, S., Radford-Weiss, I., Gross, F., Valensi, F., Delabesse, E., Macintyre, E., Sigaux, F., Soulier, J., Leiva, L. E., Wissler, M., Prinz, C., Rabbitts, T. H., Le Deist, F., Fischer, A., & Cavazzana-Calvo, M. (2003). LMO-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science, 302, 415–419.PubMedCrossRefGoogle Scholar
  34. 34.
    Yee, J. K., & Zaia, J. A. (2003). Prospects for gene therapy using HIV-based vectors. Somatic Cell and Molecular Genetics, 26, 159–174.CrossRefGoogle Scholar
  35. 35.
    Schroder, A. R., Shinn, P., Chen, H., Berry, C., Ecker, J. R., & Bushman, F. (2002). HIV-1 integration in the human genome favors active genes and local hotspots. Cell, 110, 521–529.PubMedCrossRefGoogle Scholar
  36. 36.
    Trono, D. (2000). Lentiviral vectors: Turning a deadly foe into a therapeutic agent. Gene Therapy, 7, 20–23.PubMedCrossRefGoogle Scholar
  37. 37.
    Zufferey, R., Dull, T., Mandel, R. J., Bukovsky, A., Quiroz, D., Naldini, L., & Trono, D. (1998). Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. Journal of Virology, 72, 9873–9880.PubMedGoogle Scholar
  38. 38.
    Humeau, L., et al. (2003). Initiation of a phase I clinical trial using a HIV-based lentiviral vector for the treatment of HIV/AIDS. Molecular Therapy, 7, abstract S33.Google Scholar
  39. 39.
    Clackson, T., Yang, W., Rozamus, L. W., Hatada, M., Amara, J. F., Rollins, C. T., Stevenson, L. F., Magari, S. R., Wood, S. A., Courage, N. L., Lu, X., Cerasoli, F. Jr., Gilman, M., & Holt, D. A. (1998). Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity. Proceedings of the National Academy of Sciences of the United States of America, 95, 10437–10442.PubMedCrossRefGoogle Scholar
  40. 40.
    Curran, M. A., Ochoa, M. S., Molano, R. D., Pileggi, A., Inverardi, L., Kenyon, N. S., Nolan, G. P., Ricordi, C., & Fenjves, E. S. (2002). Efficient transduction of pancreatic islets by feline immunodeficiency virus vectors1. Transplantation, 74, 299–306.PubMedCrossRefGoogle Scholar
  41. 41.
    Gallichan, W. S., Kafri, T., Krahl, T., Verma, I. M., & Sarvetnick, N. (1998). Lentivirus-mediated transduction of islet grafts with interleukin 4 results in sustained gene expression and protection from insulitis. Human Gene Therapy, 9, 2717–2726.PubMedCrossRefGoogle Scholar
  42. 42.
    Ju, Q., Edelstein, D., Brendel, M. D., Brandhorst, D., Brandhorst, H., Bretzel, R. G., Brownlee, M. (1998). Transduction of non-dividing adult human pancreatic beta cells by an integrating lentiviral vector. Diabetologia, 41, 736–739.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Beckman Research Institute of City of Hope National Medical CenterDuarteUSA

Personalised recommendations