Development of siRNA conjugates for combination treatment of acute kidney injury

开发用于联合治疗急性肾损伤的 siRNA 缀合物

• 批准号: 9789273
• 负责人: David Oupicky
• 金额: $ 41.18万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789273
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Apoptosis; Biodistribution; Biological Products; Blood Vessels; CXCR4 Receptors; CXCR4 gene; Cell Death; Cells; Charge; Chemicals; Chemistry; Chronic Kidney Failure; Cisplatin; Clinical Trials; Combined Modality Therapy; Data; Development; Disease; Drug Kinetics; Evaluation; Event; Fatty Acids; Functional disorder; Gene Silencing; Goals; Healthcare; Individual; Inflammation; Inflammatory; Injury; Injury to Kidney; Kidney; Knock-out; Knockout Mice; Medical; Metabolic; Mind; Modeling; Molecular Weight; Mus; Myocardial Ischemia; Nature; Necrosis; Operative Surgical Procedures; Organ Transplantation; Oxidative Stress; Pathologic Processes; Pathology; Pathway interactions; Performance; Pharmacologic Substance; Pharmacological Treatment; Polymers; Property; Public Health; Reperfusion Injury; Reporting; Research; Resources; Safety; Small Interfering RNA; Stroke; TP53 gene; Testing; Therapeutic; Tissues; Treatment Efficacy; Wild Type Mouse; base; burden of illness; chemokine; chemokine receptor; design; efficacy evaluation; improved; injured; innovation; kidney dysfunction; mortality; nephrotoxicity; novel; overexpression; oxidation; prevent; programs; public health relevance; renal ischemia; therapeutic evaluation; therapeutic siRNA; therapeutic target; vector

PROJECT SUMMARY Acute kidney injury (AKI) is a major unmet medical need due to the lack of effective pharmacological treatment options and significant healthcare burden of the disease. The fact that AKI mortality remains at 50-80% and has not improved in decades underscores the critical need for better treatments. Ischemia-reperfusion injury (IRI) and nephrotoxic agents (e.g., cisplatin) are critical causative factors in AKI pathophysiology. IRI is a major challenge during organ transplantation and cardiothoracic, vascular and general surgery. A wide range of pathological processes including oxidative stress, inflammation and activation of cell death programs, such as apoptosis and necrosis contribute to tissue injury and renal dysfunction in AKI. We have selected p53 and CXCR4 as potential targets for combination therapies that affect important metabolic and proinflammatory pathways in AKI. This proposal addresses the urgent need for new renoprotective treatments by developing a novel integrated siRNA delivery platform capable of selective combined inhibition of p53 and CXCR4 in AKI. The objective is to develop innovative polymer-siRNA conjugates for efficient and safe delivery of CXCR4 antagonist and anti-p53 siRNA (sip53) to proximal tubule cells of the injured kidneys. To achieve the objective, we will use polymeric CXCR4 antagonist (PCX) as the sip53 carrier and test if delivery of PCX-sip53 conjugates to CXCR4 overexpressing proximal tubule reverses ATP depletion and ameliorates inflammation, renal injury and dysfunction. We will accomplish the overall objective by pursuing the following specific aims. In aim 1, we will synthesize covalent PCX-siRNA conjugates using different linker chemistries and different molecular weight and chemical composition of PCX. We will establish the conjugate safety, CXCR4 antagonism, and the ability to deliver siRNA to proximal tubule cells due to the beneficial effect of PCX on facilitating cytoplasmic delivery of the siRNA. In aim 2, we will validate the proximal tubule-selective delivery of the conjugates by conducting comprehensive pharmacokinetic and biodistribution study and evaluating therapeutic efficacy in IRI and cisplatin models of AKI in mice. In aim 3, we will assess in detail the therapeutic efficacy of the best-performing PCX- sip53 conjugate. Using a set of mechanistic studies in wild type mice and in mice with proximal tubule-selective p53 knockout, we will illuminate how the combined inhibition of p53 and CXCR4 ameliorates the pathophysiology of AKI. Overall, the innovative design of the PCX-siRNA conjugates will establish a widely applicable approach for specific delivery of therapeutic siRNA to the injured kidney. The PCX-siRNA conjugate design will also have broader impact and serve as a prelude to efficacious treatment approaches in various other ischemic diseases including myocardial ischemia and stroke.

项目摘要 由于缺乏有效的药理治疗，急性肾脏损伤（AKI）是主要的未满足医疗需求 疾病的选择和重大医疗保健负担。 AKI死亡率保持在50-80％，并且具有 几十年来没有改善，强调了对更好治疗的关键需求。缺血再灌注损伤（IRI） 和肾毒性剂（例如，顺铂）是AKI病理生理学的关键因子。 IRI是主要的 器官移植和心胸，血管和普通手术期间的挑战。广泛的 病理过程，包括氧化应激，炎症和细胞死亡程序的激活，例如 凋亡和坏死有助于AKI的组织损伤和肾功能障碍。我们选择了p53和 CXCR4是影响重要代谢和促炎性的组合疗法的潜在靶标 Aki的途径。该提案通过开发一个新的肉体保护治疗迫切需要 新型的集成siRNA输送平台，能够选择性地抑制AKI中p53和CXCR4的组合抑制作用。这 目的是开发创新的聚合物 - siRNA结合物，以高效且安全地递送CXCR4拮抗剂 和抗p53 siRNA（SIP53）到受伤肾脏的近端小管细胞。为了实现目标，我们将使用 聚合物CXCR4拮抗剂（PCX）作为SIP53载体，并测试PCX-SIP53偶联物是否递送至CXCR4 过表达的近端小管会逆转ATP耗竭并改善炎症，肾脏损伤和 功能障碍。我们将通过追求以下特定目标来实现总体目标。在AIM 1中，我们将 使用不同的接头化学和不同的分子量和 PCX的化学组成。我们将建立共轭安全性，CXCR4拮抗作用和能力 由于PCX对促进细胞质递送的有益作用，将siRNA传递到近端小管细胞 sirna。在AIM 2中，我们将通过进行缀合物的近端小管选择递送 全面的药代动力学和生物分布研究和评估IRI和顺铂的治疗功效 小鼠AKI的模型。在AIM 3中，我们将详细评估表现最佳的PCX-的治疗功效 SIP53共轭。在野生型小鼠和具有近端小管选择性的小鼠中使用一组机械研究 p53敲除，我们将阐明p53和CXCR4的综合抑制如何改善病理生理学 Aki。总体而言，PCX-SIRNA结合物的创新设计将建立一种广泛适用的方法 特定于将治疗性siRNA送到受伤的肾脏。 PCX-SIRNA共轭设计也将具有 在其他各种缺血性疾病中的有效治疗方法的更广泛影响并成为序幕 包括心肌缺血和中风。