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: 10670211
• 负责人: ANIL K SOOD
• 金额: $ 43.61万
• 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/10670211
• 关键词: Address; Biological Models; Biology; Biomimetics; Blood Vessels; Cells; Engineering; Laboratories; Malignant Neoplasms; Membrane; Methods; Nature; Ovarian; Patients; Phase I Clinical Trials; RNA Interference; RNA Interference Therapy; RNA delivery; Small Interfering RNA; Solid Neoplasm; Surface; System; Technology; Testing; Therapeutic; Untranslated RNA; anti-tumor immune response; biomaterial compatibility; cancer cell; cancer therapy; cell type; exosome; first-in-human; in vivo; interest; liposomal delivery; nanoliposome; novel; particle; preclinical study; safety study; siRNA delivery; 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.

项目简介:

项目成果

Rucaparib in ovarian cancer: an update on safety, efficacy and place in therapy.

• DOI: 10.1177/1758835918778483
• 发表时间: 2018
• 期刊: Therapeutic advances in medical oncology
• 影响因子: 4.9
• 作者: Dal Molin GZ;Omatsu K;Sood AK;Coleman RL
• 通讯作者: Coleman RL