Targeted therapy in Type 1 diabetes

描述（由申请人提供）：由于1型糖尿病（T1D）的复杂性，成功的治疗需要一种范式转换的多学科方法。新靶点的发现、高效给药系统的开发和最先进成像技术的整合将提供对药物传递和治疗结果的实时监测。传统的治疗方法是无效的，部分原因是缺乏对胰岛的直接靶向，导致生物利用度低。这种低效率的递送需要全身性的高剂量治疗，从而产生不良的脱靶效应和毒性。为了克服这些严重的限制，我们建议开发具有成像能力的高效递送系统，专门指导基于sirna的治疗胰岛素生成β细胞。我们的定向治疗策略是基于RNAi在沉默有害疾病促进基因方面的精致特异性，以及我们在开发各种环境中用于siRNA递送的图像引导系统方面的丰富经验。在这里，我们建议开发一种图像辅助方法，使用基于右旋糖酐包被氧化铁纳米颗粒的靶向磁性纳米颗粒平台（纳米药物，ND）将siRNA治疗传递到内源性β细胞。这些将作为siRNA特异性递送到胰腺β细胞的载体，通过靶向β细胞上最近发现的标记物（ND-siRNA）。此外，这些纳米药物将作为成像报告者，通过光学和磁共振成像（MRI）在体内监测给药过程。我们将首先生成针对β细胞的荧光素酶（luc）共轭的β细胞特异性片段，并利用生物发光成像（BLI）来测试它们的in

DESCRIPTION (provided by applicant): Due to the complexity of type 1 diabetes mellitus (T1D), successful treatment will require a paradigm shifting multidisciplinary approach. The discovery of novel targets, the development of efficient drug delivery systems and the integration of state-of-the-art imaging techniques will provide real-time monitoring of both drug delivery and therapeutic outcome. Conventional therapeutics are ineffective due, in part, to the lack of directed targeting to the islets, resulting in low bioavailability. This inefficient delivey necessitates systemic administration of high doses of therapy and consequently untoward off-target effects and toxicity. To overcome these severe limitations, we propose to develop efficient delivery systems with imaging capabilities that specifically direct siRNA-based therapies to insulin-producing beta-cells. Our strategy for directed therapy is based on the exquisite specificity of RNAi for silencing harmful disease-promoting genes and our extensive experience in developing image-guided systems for siRNA delivery in various settings. Here we propose to develop an image-assisted approach for delivering siRNA therapy to endogenous beta- cells using a targeted magnetic nanoparticle platform (Nanodrug, ND) based on dextran coated iron oxide nanoparticles. These will serve as vehicles for specific delivery of siRNA to pancreatic beta-cells by targeting recently identified markers on beta-cells (ND-siRNA). In addition, these nanodrugs will function as imaging reporters for in vivo monitoring of delivery by optical and magnetic resonance imaging (MRI). We will first generate luciferase (luc)-conjugated beta-cell-specific moieties that target beta-cells and utilize bioluminescence imaging (BLI) to test their in vivo ability to label beta-cells. Next, we will attach selected targeting moieties to siRNA-containing magnetic nanoparticles and test their ability to deliver siRNA to isolated islets in culture and then in animal models of T1D concurrently with in vivo monitoring of delivery. Genes that are responsible for beta-cell apoptosis and immune recognition will be targeted with siRNA. We expect to observe a decreased T1D incidence in prevention studies and increased number of animals with restored normoglycemia in reversal studies.