Harnessing the power of exosomes for non-coding RNA delivery

项目摘要： 尽管RNA干扰(RNAi)方法有望靶向不可药物的靶点，但主要挑战 仍然存在的问题包括将siRNA特定地输送到体内感兴趣的细胞类型、稳定性差和非靶向效应。 我们一直站在解决这些问题的前沿，我的实验室开创了许多研究，使用 RNAi用于癌症治疗，并取得了与RNAi生物学相关的关键发现。我们是在 在最早证明RNAi处理机制在高比例卵巢中被解除调控的人中 和其他癌症(Merritt et al.，New Engl J Med 2008)。为了实现RNAi疗法的系统递送， 我们系统地确定了安全有效的siRNA传递方法。经过广泛的测试，我们的第一个 成功的平台利用了中性DOPC纳米脂质体给药系统(Landen等人，癌症资源2005； Ahmed等人，癌症细胞2010)，随后在多个肿瘤模型系统中进行了测试(Liu等人 等人，《自然》2015；Kim等人，Cell 2013)。拥有强大的临床前研究组合和所有必要的 基于FDA指南的安全性研究，这是第一次使用EPHARNA(EphA2靶向)进行的人类I期临床试验 DOPC中的siRNA)对实体肿瘤患者的治疗即将完成。我们在申请方面取得了长足的进步。 这项癌症治疗技术。然而，尽管我们和合成递送系统承诺 其他人已经开发出新的和生物兼容的递送策略，这些策略独立于对 血管渗漏是非常可取的。在这个项目中，我们计划开发一个仿生外体系统。 这将使癌症治疗药物能够主动输送到肿瘤微环境中。这些自然发生的 颗粒代表了一种有前途的、安全的RNAi疗法的替代方法。我们会 将RNAi包裹到这些颗粒中，并改造它们的表面膜，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和其他组织的抗肿瘤免疫反应。 癌症。如果成功，这种仿生外体系统可以迅速地更广泛地应用于其他 “无法下药”的靶子。通过R35机制提供的支持将极大地促进这一承诺，这将 否则是不可能的。

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.