Oral Delivery Vehicles for RNAi Therapies

描述（由申请人提供）：RNAi治疗的临床应用发展受到许多障碍的阻碍。最困难的障碍是如何安全、有效地将siRNA递送到特定的靶细胞类型或组织。因此，我们寻求开发可靠的siRNA口服递送技术，目标是尽快将其应用于对人类健康产生最大影响的治疗中。针对巨噬细胞的基于rnai的疗法可能会改变许多主要人类疾病的医学实践，包括1型和2型糖尿病、动脉粥样硬化、关节炎和炎症性肠病。我们之前已经描述了一种新的siRNA递送系统，该系统基于21,3- d -葡聚糖封装的siRNA颗粒（GeRPs）作为有效的口服递送载体，在体外和体内都能有效地沉默小鼠巨噬细胞中的基因。我们建议将这项技术作为治疗这些疾病和其他疾病的新方法。我们建议定量和优化包裹在GeRPs内的siRNA递送到多种组织的巨噬细胞。我们还将改进GeRP配方，以最大限度地提高靶基因沉默的效力和持续时间。最后，我们将在胰岛素抵抗和2型糖尿病小鼠模型中测试gerp介导的炎性巨噬细胞基因沉默改善疾病的能力。这些将是开发基于rnai介导的巨噬细胞基因沉默的临床疗法的关键步骤。考虑到大量的主要疾病可能被靶向，开发一种将siRNA口服递送到人类巨噬细胞的载体的影响可能是巨大的。

DESCRIPTION (provided by applicant): Development of clinical applications of RNAi therapy has been hampered by a number of hurdles. The most difficult roadblock has been achieving safe, effective delivery of siRNA to specific target cell types or tissues. We thus seek to develop reliable technology for oral siRNA delivery, with the goal of applying it as rapidly as possible to therapies which will have maximal impact on human health. RNAi-based therapies targeting macrophages could transform the practice of medicine for numerous major human diseases including type 1 and 2 diabetes, atherosclerosis, arthritis and inflammatory bowel disease. We have previously described a novel siRNA delivery system based on 21,3-D-Glucan-encapsulated siRNA Particles (GeRPs) as efficient oral delivery vehicles that potently silence genes in mouse macrophages in vitro and in vivo. We propose to develop this technology as a novel therapeutic approach for these and other diseases. We propose to quantitate and optimize the delivery of siRNA encapsulated within GeRPs to macrophages in multiple tissues. We will also improve GeRP formulations to maximize potency and duration of target gene silencing. Finally, we will test the ability of GeRP-mediated gene silencing in inflammatory macrophages to ameliorate disease in mouse models of insulin resistance and type 2 diabetes. These will be critical steps toward developing clinical therapies based on RNAi-mediated gene silencing in macrophages. The impact of developing a vehicle for orally delivering siRNA to macrophages in humans would be potentially huge given the large number of major diseases that could be targeted. PUBLIC HEALTH RELEVANCE: The use of RNA interference (RNAi) based gene silencing holds great promise as a clinical therapy for many diseases, but such applications face many hurdles including reliable methods for delivery to target tissues and organs. We have developed a novel microparticle technology for oral RNAi delivery to macrophages in living animals and demonstrated in vivo gene silencing and amelioration of inflammation. We propose here to develop this method as a clinical strategy for treating a number of important diseases in which macrophage-mediated inflammation plays a role including type 1 and 2 diabetes, atherosclerosis, arthritis and inflammatory bowel diseases.