Harnessing the power of exosomes for non-coding RNA delivery

利用外泌体的力量进行非编码 RNA 递送

• 批准号: 9388779
• 负责人: ANIL K SOOD
• 金额: $ 70.48万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-02 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9388779
• 关键词: Address; Biological Models; Biology; Biomimetics; Blood Vessels; Cells; Engineering; Human; Immune response; Laboratories; Malignant Neoplasms; Membrane; Methods; Nature; Ovarian; Patients; Phase I Clinical Trials; RNA Interference; Small Interfering RNA; Solid Neoplasm; Surface; System; Technology; Testing; Therapeutic; Untranslated RNA; base; biomaterial compatibility; cancer cell; cancer therapy; cell type; exosome; in vivo; interest; nanoliposome; novel; particle; preclinical study; safety study; tumor; tumor microenvironment

Project Abstract: Despite the promise of RNA interference (RNAi) approach for targeting undruggable targets, major challenges remain including specific delivery of siRNA into cell types of interest in vivo, poor stability and off-target effects. We have been at the forefront of addressing these issues and my laboratory has pioneered many studies using RNAi approaches for cancer treatment and has made key discoveries related to RNAi biology. We were among the first to demonstrate that RNAi processing machinery is deregulated in a high proportion of ovarian and other cancers (Merritt et al., New Engl J Med 2008). To achieve systemic delivery of RNAi therapeutics, we systematically identified safe and effective methods for siRNA delivery. After extensive testing, our first successful platform utilized the neutral DOPC nanoliposomal delivery system (Landen et al., Cancer Res 2005; Ahmed et al., Cancer Cell 2010), which has subsequently been tested in multiple tumor model systems (Liu et al., Nature 2015; Kim et al., Cell 2013). With a robust portfolio of preclinical studies and all of the requisite safety studies based on FDA guidance, a first-in-human phase I clinical trial with EPHARNA (EphA2 targeted siRNA in DOPC) is nearing completion for patients with solid tumors. We have made great strides in applying this technology for cancer therapy. However, despite the promise of synthetic delivery systems that we and others have developed, novel and biocompatible delivery strategies that are independent of reliance on vascular leakiness are highly desirable. In this project, we propose to develop a biomimetic exosomal system that will enable active delivery of cancer therapeutics to the tumor microenvironment. These naturally occurring particles represent a promising, and safe alternative approach for delivering RNAi therapeutics. We will package RNAi cargos into these particles and engineer their surface membrane to actively target distinct cell types. Finally, we will develop this approach for enhancing anti-tumor immune response in ovarian and other cancers. If successful, this biomimetic exosomal system can be rapidly applied more broadly to other “undruggable” targets. Support through the R35 mechanism will greatly facilitate this undertaking, which would not otherwise be possible.

项目摘要： 尽管RNA干扰有望（RNAI）靶向不良目标，但仍有主要挑战 保留在体内感兴趣的细胞类型，稳定性和脱靶效应中，包括特定的siRNA输送。 我们一直处于解决这些问题的最前沿，我的实验室已经开创了许多研究 RNAi方法进行癌症治疗，并已成为与RNAi生物学有关的关键发现。我们是 在第一个证明RNAi加工机械以很大比例的卵巢中进行管制的 和其他癌症（Merritt等人，New Engl J Med 2008）。为了实现RNAi治疗的系统性递送， 我们系统地确定了siRNA输送的安全有效方法。经过广泛的测试，我们的第一个 成功的平台利用了中性DOPC纳米脂质体递送系统（Landen等，Cancer Res 2005； Ahmed等人，癌细胞2010），随后在多个肿瘤模型系统中进行了测试（Liu et Al。，Nature 2015; Kim等人，Cell 2013）。通过临床前研究的强大组合和所有必要 基于FDA指南的安全研究，这是一项与Epharna的第一阶段临床试验（Epha2针对的 对于实体瘤患者，DOPC中的siRNA即将完成。我们在申请方面取得了长足的进步 这项用于癌症治疗的技术。然而，尽管我们和我们和 其他人则制定了新颖和生物相容性的交付策略，这些策略独立于救济 血管泄漏是非常可取的。在这个项目中，我们建议开发仿生的外泌体系统 这将使癌症治疗能够积极地递送到肿瘤微环境中。这些天然发生 颗粒代表了提供RNAi治疗的一种希望和安全的替代方法。我们将 将RNAi Cargos包装到这些颗粒中，并设计其表面膜以主动靶向不同的细胞 类型。最后，我们将开发这种方法来增强卵巢及其他的抗肿瘤免疫反应 癌症。如果成功，这种仿生的外泌体系统可以更广泛地应用于其他 “不可能”的目标。通过R35机制的支持将极大地促进这项事业，这将 否则不可能。