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RNA aptamers as cell surface receptor agonists and siRNA delivery agents

RNA适体作为细胞表面受体激动剂和siRNA递送剂

基本信息

批准号：
7737559
负责人：
BRUCE ALAN SULLENGER
金额：
$ 25.9万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-24 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7737559
关键词：
Age related macular degeneration Agonist Apoptosis Aptamer Technology Cancer Vaccines Cancer cell line Cell Culture Techniques Cell Line Cell Proliferation Cell Surface Receptors Cell surface Cells Chimera organism Clinical Trials Dendritic Cells Development Disease Drug Formulations Erythrocytes Erythropoiesis FDA approved Factor IXa Funding Genes Glutamate Carboxypeptidase II Grant Health Immune response Immunotherapy In Vitro Knowledge Malignant Neoplasms Malignant neoplasm of prostate Mammalian Cell Mediating Methods Modeling Mus Patients Population Proteins Proto-Oncogene Protein c-kit RNA RNA Interference Receptor Activation Research Personnel Safety Series Signal Transduction Small Interfering RNA Surface T-Cell Lymphoma T-Cell Proliferation T-Lymphocyte Technology Testing Therapeutic Agents Translating Treatment Efficacy Vaccines Vascular Endothelial Growth Factors Work aptamer base cancer cell cancer therapy cost effectiveness cytokine improved in vivo inhibitor/antagonist leukemia leukemia/lymphoma neoplastic cell novel novel strategies novel therapeutics receptor receptor binding targeted delivery theories tumor

项目摘要

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

RNA适体已经针对多种蛋白质产生，包括一些细胞表面的蛋白质