Oral Delivery Vehicles for RNAi Therapies

描述(由申请人提供)：RNAi疗法的临床应用发展受到许多障碍的阻碍。最困难的障碍一直是实现安全、有效地将siRNA传递到特定的靶细胞类型或组织。因此，我们寻求开发可靠的口服siRNA传递技术，目标是尽快将其应用于对人类健康具有最大影响的治疗。基于RNAi的针对巨噬细胞的治疗可以改变人类许多主要疾病的药物实践，包括1型和2型糖尿病、动脉粥样硬化、关节炎和炎症性肠道疾病。我们之前已经描述了一种基于21，3-D-葡聚糖包裹的siRNA颗粒(GeRPs)的新型siRNA递送系统，它是一种高效的口服递送载体，在体外和体内都能有效地沉默小鼠巨噬细胞中的基因。我们建议开发这项技术，作为这些和其他疾病的一种新的治疗方法。我们建议定量和优化包裹在GeRPs中的siRNA递送到多个组织中的巨噬细胞。我们还将改进GERP的配方，以最大限度地提高靶基因沉默的效力和持续时间。最后，我们将测试炎症巨噬细胞中GERP介导的基因沉默对改善胰岛素抵抗和2型糖尿病小鼠模型疾病的能力。这些将是开发基于RNAi介导的巨噬细胞基因沉默的临床治疗的关键步骤。考虑到可能针对的大量重大疾病，开发一种向人类巨噬细胞口服siRNA的载体的影响可能是巨大的。 公共卫生相关性：使用基于RNA干扰(RNAi)的基因沉默作为许多疾病的临床治疗具有很大的前景，但这种应用面临许多障碍，包括向目标组织和器官传递的可靠方法。我们开发了一种新的微粒子技术，将RNAi口服到活动物的巨噬细胞中，并在体内展示了基因沉默和炎症改善。我们建议将这种方法发展为一种临床策略，用于治疗一些由巨噬细胞介导的炎症起作用的重要疾病，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。

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.