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 (RNAi) 方法有望用于靶向不可成药的靶标，但仍面临重大挑战 仍然包括将 siRNA 特异性递送到体内感兴趣的细胞类型、稳定性差和脱靶效应。 我们一直处于解决这些问题的最前沿，我的实验室开创了许多使用 RNAi 方法用于癌症治疗，并取得了与 RNAi 生物学相关的重要发现。 率先证明 RNAi 加工机制在高比例卵巢中失调 和其他癌症（Merritt 等人，New Engl J Med 2008）。 经过广泛的测试，我们系统地确定了安全有效的 siRNA 递送方法。 成功的平台利用了中性 DOPC 纳米脂质体递送系统（Landen 等人，Cancer Res 2005； Ahmed 等人，Cancer Cell 2010），随后在多个肿瘤模型系统中进行了测试（Liu 等人，2010）。 al.，Nature 2015；Kim 等人，Cell 2013）。 基于 FDA 指导的安全性研究，这是一项针对 EPHARNA（EphA2 靶向）的首次人体 I 期临床试验 siRNA in DOPC）在实体瘤患者中的应用已接近完成，我们在应用方面取得了长足进步。 然而，尽管我们和合成递送系统有希望。 其他人已经开发出新颖且生物相容的递送策略，这些策略独立于对 在这个项目中，我们建议开发一种仿生外泌体系统。 这将使癌症治疗药物能够主动递送到肿瘤微环境中。 颗粒代表了一种有前途且安全的 RNAi 治疗替代方法。 将 RNAi 货物包装到这些颗粒中，并改造其表面膜以主动靶向不同的细胞 最后，我们将开发这种方法来增强卵巢和其他部位的抗肿瘤免疫反应。 如果成功，这种仿生外泌体系统可以迅速更广泛地应用于其他癌症。 通过 R35 机制提供的支持将极大地促进这一目标的实现。 否则不可能。