Oral Delivery Vehicles for RNAi Therapies

RNAi治疗的临床应用发展一直受到许多障碍的阻碍。这个 最困难的障碍是实现安全、有效地将siRNA递送到特定的靶细胞类型或 纸巾。因此，我们寻求开发可靠的口服siRNA传递技术，目标是将其应用于 尽快采取对人类健康有最大影响的治疗方法。基于RNAi的治疗 以巨噬细胞为靶点可以改变人类许多重大疾病的医学实践 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。我们有 先前描述了一种基于B1，3-D-葡聚糖包埋的siRNA递送系统 颗粒(GeRPs)作为高效的口服载体，有效地沉默了小鼠巨噬细胞中的基因 体外和体内。我们建议开发这项技术作为一种治疗这些疾病的新方法 其他疾病。我们建议对包裹在GeRPs中的siRNA的递送进行量化和优化 到多个组织中的巨噬细胞。我们还将改进GERP配方，以最大限度地提高效力和 靶基因沉默的持续时间。最后，我们将测试GERP介导的基因沉默在 炎性巨噬细胞改善胰岛素抵抗和2型小鼠的疾病 糖尿病。这些将是开发基于RNAi介导的基因的临床治疗的关键步骤 巨噬细胞中的沉默。研制口服siRNA载体对巨噬细胞的影响 考虑到可能成为目标的大量重大疾病，人类的风险可能会很大。

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 B1,3-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.