Gene Medicine and Therapy

Translational medicine from bench to bedside has high priority today. We have previously developed two approaches in the laboratory, which led to clinical trials in patients.

In collaboration with Apollon Co, USA a DNA vaccine against HIV was developed under direction of Karin Moelling and transfered to Zurich, which led to the first DNA vaccine clinical trial in Europe Weber 2001.pdf. Four patients were vaccinated against HIV and a follow-up for several years did not indicate any adverse events.

Another approach was taken by developing a gene medicine with plasmid DNA coding for interleukin 12. IL-12 DNA vacciniation was tested in mice and grey horses and led to an investigator-driven clinical trial with nine patients with late stage malignant melanoma Heinzerling 2005.pdf. Follow-up papers indicated that various combinations lead to better preclinical success, but has not been tested in humans yet. IL-12 GMP DNA is available for collaboration. A patent for using IL-12 coding DNA is issued (Unitectra, Technology Transfer Office, University of Zurich). Furthermore IL-12 plasmid DNA was used as immune therapy against tuberculosis in mice Lowrie 1999.

A DNA vaccination approach was also taken with a plasmid coding for the Abeta protein of Alzheimer’s disease, which resulted in immune response in mice used for isolation of monoclonal antibodies. Application in mice resulted in reduction of amyloid plaques Schulz 2004.pdf. The monoclonal antibodies can be used for further drug development upon request.

Publications about Gene Medicine and Therapy

  1. *Coney, L., Wang, B., Ugen, K.E., Boyer, J., McCallus, D., Srikantan, V., Agadjanyan, M., Patchuk, C.J., Herold, K., Merva, M., Gilbert, L., Dang, K., Moelling, K., Newman, M., Williams, W.V., and Weiner, D.B. Facilitated DNA inoculation induces anti-HIV-1 immunity in vivo. Vaccine 12, 1545-1550 (1994).
  2. Wang, B., Boyer, J., Srikantan, V., Ugen, K., Agadjanian, M., Merva, M., Gilbert, L., Dang, K., McCallus, D., Moelling, K., Carrano, R., Williams, W.V., Coney, L. and Weiner, D. DNA Inoculation Induces cross clade Anti-HIV-1 responses. In: “Annals of the New York Acadeny of Science: DNA Vaccines: A new era in Vaccinology“ (M.A. Liu, M.R. Hillemann and R. Kurth, eds.), 186-197, New York Academy of Sciences (1995)
  3. Moelling, K. DNA for genetic vaccination and therapy. Cytokines Cellular and Molecular Therapy 3, 127-136 (1997).
  4. Moelling, K. Naked DNA – the poor man’s gene therapy? Gene Therapy 5, 573-574 (1998) (invited editorial).
  5. Heinrich, J., Strack, B., Nawrath, M., Pavlovic, J., Moelling, K Immunization with naked DNA coexpressing antigen and cytokine via IRES, in DNA vaccines: Methods and Protocols, eds. Douglas B.Lowrie and Robert Whalen, Methods in Molecular Medicine (1998), series editor John W. Walker, 335-344 (1999).
  6. Nawrath, M., Heinrich, J., Strack, B., Pavlovic, J. and Moelling, K. A DNA vaccine against malignant melanoma coexpressing antigen and cytokine. Adv Exp Med Biol, 451, 305-10 (1998).
  7. Nawrath, M., Pavlovic, J., Dummer, R., Schultz, J., Strack, B., Heinrich, J. and Moelling, K. Reduced melanoma tumor formation in mice immunized with DNA expressing the melanoma-specific antigen gp100/pmel17. Leukemia 13, Suppl. 1, S48-S51 (1999).
  8. *Schultz, J., Pavlovic, J., Strack, B., Nawrath, M. and Moelling, K. Long-lasting anti-metastatic efficiency of IL-12-encoding plasmid DNA. Human Gene Therapy 10, 407-417 (1999).
  9. Operschall, E., Schuh, T., Heinzerling, L., Pavlovic, J. and Moelling, K. Enhanced protection against viral infection by co-administration of plasmid DNA coding for viral antigen and cytokines in mice. Journal of Clinical Virology 13, 17-27 (1999).
  10. ***Lowrie, D.B., Tascon, R.E., Bonato, V.L.D., Lima, V.M.F., Faccioli, L.H., Stavropoulos, E., Colston, M.J., Hewinson, R.G., Moelling, K. and Silva, C.L. Therapy of tuberculosis in mice by DNA vaccination. Nature 400, 269-271 (1999).
  11. Schuh, T., Schultz, J., Moelling, K. and Pavlovic, J. DNA-based vaccine against La Crosse virus: protective immune response mediated by neutralizing antibodies and CD4+ T cells. Human Gene Therapy 10, 1649-1658 (1999).
  12. Dummer, R., Yue F.-Y., Döhring, Ch., Pavlovic, J., Moelling K., Geertson, R., Burg, G. (1998). Immune stimulatory potential of B7.1 and B7.2 retrovirally transduced melanoma cells: B7.2 suppression by interleukin 10. British Journal of Cancer 77 (9), 1413-1419.
  13. Schultz, J., Pavlovic, J., Strack, B., Nawrath, M. and Moelling, K. (1999). Long-lasting anti-metastatic efficiency of IL-12-encoding plasmid DNA. Human Gene Therapy 10, 407-417
  14. Operschall, E., Schuh, T., Heinzerling, L., Pavlovic, J. and Moelling, K. (1999). Enhanced protection against viral infection by co-administration of plasmid DNA coding for viral antigen and cytokines in mice. Journal of Clinical Virology 13, 17-27.
  15. Di Carlo, E., Comes, A., Basso, S., De Ambrosis, A., Meazza, R., Musiani, P., Moelling, K., Albini, A. and Ferrini, S. (2000). The combined action of IL-15 and IL-12 gene transfer can induce tumor cell rejection without T and NK cell involvement. The Journal of Immunology 165, 3111-3118.
  16. Schultz, J., Pavlovic, J. and Moelling, K. (2000). Immune modulation in cancer using DNA inoculation – antitumour effect of interleukin-12. Developments in Biologicals 104, 109-114.
  17. Schultz, J., Pavlovic, J. and Moelling, K. Immune modulation in cancer using DNA inoculation – antitumour effect of interleukin-12. Developments in Biologicals 104, 109-114 (2000).
  18. Di Carlo, E., Comes, A., Basso, S., De Ambrosis, A., Meazza, R., Musiani, P., Moelling, K., Albini, A. and Ferrini, S. The combined action of IL-15 and IL-12 gene transfer can induce tumor cell rejection without T and NK cell involvement. The Journal of Immunology 165, 3111-3118 (2000).
  19. *Schultz, J., Heinzerling, L., Pavlovic, J. and Moelling, K. Induction of long-lasting cytokine effect by injection of IL-12 encoding plasmid DNA. Cancer Gene Therapy 7, 1557-1565 (2000).
  20. Schultz, J., Dollenmaier, G. and Moelling, K. Update on antiviral DNA vaccine research. Intervirology 43, 197-217 (2000).
  21. Pavlovic, J., Schultz, J., Hefti, H.P., Schuh, T. and Moelling, K. DNA vaccination against La Crosse Virus. Intervirology 43, 312-321 (2000).
  22. Operschall, E., Pavlovic, J., Nawrath, M. and Moelling, K. Mechanism of protection against influenza A virus by DNA vaccine encoding the hemagglutinin Gene. Intervirology 43, 322-330 (2000).
  23. ***Weber, R., Bossart, W., Cone, R., Luethy, R., Moelling, K. Phase I clinical trial with HIV-1 gp160 plasmid vaccine in HIV-1-infected asymptomatic subjects. Eur. J. Clin. Microbiol. Infect. Dis. 20, 800-803 (2001).
  24. **Heinzerling, L., Feige, K., Rieder, S., Akens, M., Dummer, R., Stranzinger, G., Moelling, K. (2001). Tumor regression induced by intratumoral injection of DNA coding for human interleukin 12 into melanoma metastases in gray horses. Journal of Molecular Medicine 78, 692-702.
  25. Heller, R., Schultz, J., Lucas, ML., Jaroszeski, MJ., Heller, LC., Gilbert, RA., Moelling, K. and Nicolau, C. (2001). Intradermal delivery of interleukin-12 plasmid DNA by in vivo electroporation. DNA Cell Biol. 20, 21-26.
  26. Heinzerling, L., Dummer, R., Pavlovic, J., Schultz, J., Burg, G., Moelling, K. (2002). Tumor regression of human and murine melanoma after intratumoral injection of IL-12 encoding plasmid DNA in mice. Exp. Derm. 11, 232-241.
  27. Heinrich, J., Schultz, J., Bosse, M., Ziegelin, G., Lanka, E., Moelling, K. (2002) Linear closed mini DNA generated by the procaryotic cleaving-joining enzyme TelN. J. Mol. Med. 80, 648-654.
  28. Ladell, K., Heinrich, J., Schweneker, M., Moelling, K. (2003). A combination of plasmid DNAs encoding murine Flk-1 extracellular domain, murine IL-12 and murine IP-10 lead to tumor regression and survival in melanoma-bearing mice. J. Mol. Med. 81, 271-278.
  29. Keyser, J., Schultz, J., Ladell, K., Elzaouk, L., Heinzerling, L., Pavlovic, J., Moelling K. (2004). IP-10-encoding plasmid DNA therapy exhibits antitumor and antimetastatic efficiency. Experimental Dermatology, 13, 380-390.
  30. Schultz, J., Salzer, U., Mohajeri, M.H., Franke, D., Heinrich, J., Pavlovic, J., Wollmer, M.A., Nitsch, R., Moelling K. Antibodies from a DNA-peptide vaccination decrease the brain amyloid burden in a mouse model of AD J. Mol. Med., 82, 706-714 (2004).
  31. Morini, M., Albini, A., Lorusso, G., Moelling, K., Lu, B., Cilli, M., Ferrini, S., Noonan, D.M. (2004). Prevention of angiogenesis by naked DNA IL-12 gene transfer: angioprevention by immuno-gene therapy. Gene Ther. 11, 3, 284-91.
  32. Schultz, J., Salzer, U., Mohajeri, M.H., Franke, D., Heinrich, J., Pavlovic, J., Wollmer, M.A., Nitsch, R., Moelling K. Antibodies from a DNA-peptide vaccination decrease the brain amyloid burden in a mouse model of AD J. Mol. Med., 82, 706-714 (2004).
  33. ***Heinzerling, L., Burg, G., Dummer, R., Oberholzer, P., Schultz, J., Elzaouk, L., Pavlovic. J., Moelling. K. Intratumoral Injection of DNA Encoding Human Interleukin-12 into Patients with Metastatic Melanoma: Clinical Efficacy Human Gene Therapy 16, 35-48 (2005).
  34. Elzaouk, L., Moelling, K., Pavlovic, J. (2006). Antitumor activity of mesenchymal stem cells producing murine IL-12 in a mouse melanoma model. Exp. Dermatology 15, 865-874.
  35. Elzaouk, L., Pavlovic, J., Moelling, K. (2006). Analysis of antitumor activity elicited by vaccination with combinations of IL-12 DNA with gp100 DNA or the chemokine CCL21 in vivo. Hu Gene Ther 17, 859-870.
  36. Usluoglu, N., Pavlovic, J., Moelling, K. and Radziwill, G. (2007). RIP2 mediates LPS-induced p-38 and IκBα signaling including IL-12 p40 expression in human monocyte-derived dendritic cells Eur. J. Immunol. 37, 2317-2325.
  37. Moelling, K :Editor of Book on “Viral DNA Vaccines” in „Intervirology“, S. Karger AG, Basel, 43, 4-6, 2000. Editor of Book on “Viral DNA Vaccines” in „Intervirology“, S. Karger AG, Basel, 43, 4-6, 2000