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

• 批准号: 7847451
• 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
• 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/7847451
• 关键词: Age related macular degeneration; Agonist; Animals; 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; Data; 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; Modeling; Mus; Population Research; Proteins; Proto-Oncogene Protein c-kit; Public Health; RNA; RNA Interference; Research Personnel; Safety; Series; Signal Transduction; Small Interfering RNA; Surface; T-Cell Lymphoma; T-Cell Proliferation; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Agents; Translating; Treatment Efficacy; United States; Vaccines; Vascular Endothelial Growth Factors; Work; aptamer; base; cancer cell; cancer immunotherapy; cancer therapy; cost effectiveness; cytokine; improved; in vivo; inhibitor/antagonist; leukemia; leukemia/lymphoma; mouse model; neoplastic cell; novel; receptor; receptor binding; targeted delivery; tumor

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

已针对多种蛋白质（包括一些细胞表面蛋白质）生成了RNA适体 受体。一般而言，此类适体在体外和体内均充当其靶蛋白的有效抑制剂。 此外，这些拮抗性适体中的一些已经在临床试验中进行了评估，包括一个我们正在进行的研究。 一种是针对因子IXa开发的，另一种已被FDA批准用于治疗年龄相关性黄斑 退化然而，直到去年，还没有适体被描述为可以作为激动剂。在这 我们探索了适体激活细胞表面受体的能力。在初步结果部分 我们描述了一系列的研究，证明我们针对 T细胞上的两种不同受体4-伊布和0X 40能够激活原代鼠T细胞上的这些受体， 导致T细胞增殖、细胞因子释放和增强的抗肿瘤疫苗活性的小鼠肿瘤细胞 免疫治疗模型据我们所知，这是第一批被鉴定的两种适体， 充当激动剂。在这里，我们正在寻求支持，以评估这两个激动性适体的活性，以及 为了确定我们最近制造的针对干细胞因子受体c-Kit的第三种适体是否可以 也可作为激动剂并激活干细胞因子受体和红细胞生成。这些适体的分析将 包括评估它们将siRNA递送至原代1-细胞和T-细胞淋巴瘤和白血病细胞系能力 (0X40和4- 1BB适体）和红细胞前体和c-Kit阳性肿瘤细胞（cKit适体）。 需要介导小干扰RNA（siRNA）的靶向递送的技术来改善靶向递送。 基于siRNA的治疗剂的疗效、安全性和成本效益