RNA aptamers have been generated against a variety of proteins including a few cell surface receptors. In general such aptamer act as potent inhibitors of their target proteins both in vitro and in vivo. Moreover, a few of these antagonistic aptamers have been evaluated in clinical trials including one we developed against factor IXa and one that has been approved by the FDA for treating age related macular degeneration. However until last year, no aptamer has been described that can act as an agonist. In this proposal we explore the ability of aptamers to activate cell surface receptors. In the preliminary results section we describe a series of studies demonstrating that dimeric versions of aptamers that we have made against two different receptors on T-cells, 4-IBB and 0X40, are able to activate these receptors on primary murine T cells resulting in T-cell proliferation, cytokine release and enhanced antitumor vaccine activity in murine tumor immunotherapy models. To our knowledge these are the first two aptamers that have been identified that can act as agonists. Here we are seeking support to evaluate the activity of these two agonistic aptamers as well as determine whether a third aptamer that we have recently made against stem cell factor receptor, c-Kit, can also act as an agonist and activate stem cell factor receptor and erythropoiesis. Analysis of these aptamers will include assessing their ability to deliver siRNAs to primary 1-cells and T-celi lymphoma and leukemia cell lines (0X40 and 4-1 BB aptamers) and erythrocyte precursors and c-Kit positive tumor cells (cKit aptamer). Technologies that mediate targeted delivery of small interfering RNAs (siRNAs) are needed to improve the therapeutic efficacy, safety and cost effectiveness of siRNA-based therapeutic agents

Public Health Relevance

This project proposes to develop RNA therapeutic molecules to treat a variety of cancers and other disorders. Since cancer remains a significant public health issue in the United States, if funded the proposed studies could yield novel therapies that could improve the health of the U.S. population.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129190-04
Application #
8333428
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Fu, Yali
Project Start
2009-05-24
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$251,191
Indirect Cost
$90,171
Name
Duke University
Department
Surgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Pratico, Elizabeth D; Sullenger, Bruce A; Nair, Smita K (2013) Identification and characterization of an agonistic aptamer against the T cell costimulatory receptor, OX40. Nucleic Acid Ther 23:35-43
Mi, Jing; Liu, Yingmiao; Rabbani, Zahid N et al. (2010) In vivo selection of tumor-targeting RNA motifs. Nat Chem Biol 6:22-4
Wang, Jialiang; Wakeman, Timothy P; Lathia, Justin D et al. (2010) Notch promotes radioresistance of glioma stem cells. Stem Cells 28:17-28