Aptamer Targeted siRNA to Prevent Attenuation or Suppression of T-Cell Function
Eli Gilboa
Problem
Limited specificity of drugs and the need to reach all, or the vast majority, of the tumor cells disseminated throughout the body are the two major challenges in developing effective treatments for cancer. This work addresses both fundamental issues in the treatment of cancer.
Solution
The development of a clinically applicable, broadly useful, and cost effective approach to counter immune attenuating/suppressive pathways using RNAi-mediated gene silencing (siRNA/shRNA). The centerpiece of this approach is to target the drug (the siRNA) to the appropriate immune cells in vivo using nuclease-resistant oligonucleotide-based aptamers.
Competitive Advantage
Use of aptamers to target gene silencing to the appropriate cells in vivo provides a drug/reagent that can be chemically synthesized in cell-free systems which significantly enhances the clinical applicability of this targeting approach (compared to antibody-based targeting). Consequently, the amount of siRNA reagent needed for treatment can be drastically reduced which also reduces treatment cost and toxicity.
Aptamers are superior to antibodies for the following reasons:
1) Can be synthesized chemically in cell free system;
2) Have a cost effective manufacturing process;
3) Have a simple regulatory approval process for clinical use;
4) and since they are not attached to protein carriers, they should be much less immunogenic than antibodies.
Furthermore, a key advantage of immune modulating drugs, whether targeted or not, is that only a fraction of the target cells need to be accessed in vivo for the approach to be successful.
Applications
1) Tumor immunity (for example to enhance immunogenicity and antigenicity);
2) Anti-viral immunity;
3) Autoimmunity;
4) Inflammation;
5) Transplantation
Patent Status
International Patent Application No.
WO2009046104
entitled "APTAMER-TARGETED SIRNA TO PREVENT ATTENUATION OR SUPPRESSION OF T CELL FUNCTION" was published on April 9, 2009.
Licensing Opportunity
The University of Miami is seeking collaborative research and licensing options.
About the Inventors
Eli Gilboa Ph.D., is the Director of the Dodson Interdisciplinary Immunotherapy Institute and Co-director of the Tumor Immunobiology & Immunotherapy Program at University of Miami Miller School of Medicine. Dr. Gilboa is one of the nation's preeminent translational researchers bridging basic biomedical science and clinical research. Dr. Gilboa was one of the early pioneers of the fledgling field of gene therapy and played a key role at the dawn of this new era, developing the first generation of retroviral vectors used in the first human gene therapy trial by Dr. Rosenberg, Anderson and their colleagues. In a seminal study heralding the application of short RNA molecules (aptamers) for human therapy, he introduced the concept of RNA decoys to render cells resistant to HIV infection. Dr. Gilboa was also one of the early pioneers in the fields of cancer gene therapy demonstrating the potential of gene modified tumor cells as cancer vaccines. His current program is devoted to the development of multi-pronged strategies to engender protective immunity in the setting of cancer and infectious disease, developing potent vaccination strategies, manipulating immunomodulatory pathways, and targeting immune evasion mechanisms.
Dr. Gilboa received his Ph.D. in molecular biology at the Weizmann Institute, Rehovot, Israel, was an assistant professor in the Department of Molecular Biology at Princeton University, USA, from 1980-1986, and served as an associate member of the Memorial Sloan-Kettering Institute for Cancer Research Molecular Biology Program from 1986-1993. In 1993 Dr. Gilboa joined Duke University Medical Center as the Joseph and Dorothy Beard Professor of Experimental Surgery and Immunology and Director of the Center for Genetic and Cellular Therapies overseeing the development and clinical implementation of novel gene- and cell-based therapies. In September 2006, Dr. Gilboa joined the Sylvester Comprehensive Cancer Center and the Department of Microbiology & Immunology, Miller School of Medicine, University of Miami.
Selected References
McNamara, J. O., D. Kolonias, F. Pastor, R.S. Mittler, L. Chen, P.H. Giangrande, B. Sullenger and E. Gilboa. Costimulation of CD8+ T cells and inhibition of tumor growth with multivalent 4-1BB binding aptamers. J. Clin. Invest., 118:376-386, 2008.
Gilboa, E. DC-based cancer vaccines. J Clin Invest 117:1195-1203,2007.
Nair, S., D. Boczkowski, M. Fassnacht, D. Pisetsky, and E. Gilboa.. Vaccination against the forkhead family transcription factor Foxp3 enhances tumor immunity. Cancer Res 67:371-380, 2007.
McNamara, J.O., 2nd, E.R. Andrechek, Y. Wang, K.D. Viles, R.E. Rempel, E. Gilboa, B.A. Sullenger, and P.H. Giangrande. Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat Biotechnol 24:1005-1015, 2006.
Dannull, J., Z. Su, D. Rizzieri, B.K. Yang, D. Coleman, D. Yancey, A. Zhang, P. Dahm, N. Chao, E. Gilboa, and J. Vieweg. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest. 115:3623-3633, 2005.
Gilboa, E. The promise of cancer vaccines. Nat Rev Cancer 4:401-411, 2004.
Gilboa, E., and J. Vieweg. Cancer immunotherapy with mRNA-transfected dendritic cells. Immunol Rev 199:251-263, 2004.
Santulli-Marotto, S., S.K. Nair, C. Rusconi, B. Sullenger, and E. Gilboa. Multivalent RNA aptamers that inhibit CTLA-4 and enhance tumor immunity. Cancer Res 63:7483-7489, 2003.
Nair, S., D. Boczkowski, B. Moeller, M. Dewhirst, J. Vieweg, and E. Gilboa. Synergy between tumor immunotherapy and antiangiogenic therapy. Blood 102:964-971, 2003.
Nair, S.K., A. Heiser, D. Boczkowski, A. Majumdar, M. Naoe, J.S. Lebkowski, J. Viweg, and E. Gilboa. Induction of cytotoxic T cell responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells. Nature Medicine 6:1011-1017, 2000.
