Application of Brain-Targeted Anti-inflammatory RNA Nanoparticle for Ischemic Stroke Therapy

脑靶向抗炎RNA纳米粒在缺血性脑卒中治疗中的应用

基本信息

批准号：
8953140
负责人：
Jiukuan Hao
金额：
$ 20.55万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8953140
关键词：
Address Adhesions Affect Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Area Blood - brain barrier anatomy Blood Vessels Brain Brain Diseases Brain Injuries Cell Adhesion Cell Adhesion Molecules Cell physiology Cells Cerebral Ischemia Cessation of life Clinical Trials Complex Data Development Disease Drug Delivery Systems Endothelial Cells Endothelium Enzymes Glucose Goals Health Human Immune response Immunity In Vitro Inflammation Inflammatory Response Intercellular adhesion molecule 1 Ischemic Stroke Lead Leukocytes Mediating Middle Cerebral Artery Occlusion Modeling Mus Nanotechnology Neuraxis Neuronal Injury Neurons Outcome Oxygen Pathology Patients Pharmaceutical Preparations Play Positioning Attribute RNA RNA Phages RNA Transport Reperfusion Therapy Reporting Research Role Small Interfering RNA Stroke System Technology Therapeutic Therapeutic Effect Tissues Transferrin Receptor Translating Up-Regulation aptamer base clinical application density deprivation enlimomab in vivo in vivo Model monocyte nanoparticle novel novel strategies novel therapeutics protective effect public health relevance statistics stroke therapy targeted delivery treatment strategy vector

项目摘要

DESCRIPTION (provided by applicant): Although some of the cellular mechanisms of neuronal injury after ischemic stroke are fairly well understood, the neuronal death after ischemic stroke cannot be well controlled because of a lack of efficient treatments. The long-term goal of my research is to develop an effective strategy for ischemic stroke therapy. The proposed research is focused on targeting the post- ischemic inflammation at blood-brain barrier (BBB) in search of new approaches for stroke therapy. We propose a novel RNA nanoparticle, 3WJ-pRNA/2siICAM-FB4, consisting of one RNA aptamer (FB4), two ICAM-1 siRNA and a 3-way junction of packaging RNA (3WJ-pRNA) of bacteriophage phi29. FB4 is a RNA aptamer specific to transferrin receptor (TfR) that can recognize TfRs at the BBB and facilitate RNA nanoparticle delivery into brain endothelial cells. Once the 3WJ-pRNA/2siICAM-FB4 enters the cell, the siRNAs will be released and knockdown ICAM-1 expression leading to inhibition of inflammatory responses at the BBB. The pRNA 3-way junction serves as the core for holding FB4 and siRNAs together without disrupting the folding of either of the attached payload. We will use mouse transient ischemic stroke model in vivo and oxygen-glucose deprivation in primary brain endothelial cells in vitro to demonstrate the feasibility of this vascular targeting strategy for treatment of ischemic stroke. Our central hypothesis is that the 3WJ-pRNA/2siICAM-FB4 has therapeutic effects on ischemic stroke by inhibition of post-ischemic inflammation. Specific Aims: Aim 1: Determine pharmacological activity of 3WJ-pRNA/2siICAM-FB4 in vitro. Aim 2: Evaluate protective effect of 3WJ- pRNA/2siICAM-FB4 in transient ischemic stroke model in vivo. This project will develop a novel brain-targeted RNA therapeutics for therapy of ischemic stroke, and this approach could be broadly applied for therapy of diseases affecting the BBB and the central nervous system (CNS).

描述（由适用提供）：尽管缺血性中风后神经元损伤的某些细胞机制已被充分了解，但由于缺乏有效的治疗，缺血性中风后的神经元死亡无法得到很好的控制。我的研究的长期目标是制定缺血性中风疗法的有效策略。拟议的研究重点是针对血脑屏障（BBB）的缺血后感染，以寻找中风治疗的新方法。我们提出了一种新型的RNA纳米颗粒，3WJ-PRNA/2SIICAM-FB4，由一个RNA APATMER（FB4），两个ICAM-1 siRNA和一个包装RNA（3WJ-PRNA）的3路交界处组成。 FB4是特定于转铁蛋白受体（TFR）的RNA APATMER，可以识别BBB处的TFR并促进RNA纳米颗粒递送到脑内皮细胞中。一旦3WJ-PRNA/2SIICAM-FB4进入细胞，将释放siRNA并敲低ICAM-1表达，从而导致BBB抑制炎症反应。 PRNA 3向交界处是将FB4和siRNA固定在一起的核心，而无需破坏任何一个附件有效载荷的折叠。我们将在体外使用小鼠短暂性缺血性卒中模型，并在体外使用氧葡萄糖剥夺，以证明这种血管靶向治疗缺血性中风的可行性。我们的中心假设是3WJ-PRNA/2SIICAM-FB4通过抑制缺血后注射对缺血性中风具有治疗作用。具体目的：目标1：在体外确定3WJ-PRNA/2SIICAM-FB4的药物活性。 AIM 2：评估3WJ-PRNA/2SIICAM-FB4在体内短暂性缺血性中风模型中的受保护作用。该项目将开发出一种新型的脑部脑部中风治疗的RNA疗法，并且该方法可以广泛地用于影响BBB和中枢神经系统（CNS）的疾病治疗。