Treatment of Alzheimer’s Disease using Ultrasound-Targeted Microbubble Cavitation-Mediated Blood Brain Barrier Opening to Facilitate Drug Delivery to the Brain

使用超声靶向微泡空化介导的血脑屏障打开促进药物输送至大脑来治疗阿尔茨海默病

• 批准号: 10462037
• 负责人: Grace Conway
• 金额: $ 5.18万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-27 至 2027-07-26
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462037
• 关键词: Address; Adherens Junction; Adverse effects; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; American; Antibodies; Area; Astrocytes; Biology; Blood - brain barrier anatomy; Blood capillaries; Brain; Calcium; Caregivers; Cells; Coculture Techniques; Confocal Microscopy; Contrast Media; Data Analyses; Deposition; Development; Dextrans; Disease; Dose; Drug Delivery Systems; Drug Design; Drug Modelings; Drug usage; Electrical Resistance; Endothelial Cells; Endothelium; Enzymes; Event; Experimental Designs; FDA approved; Failure; Family; Goals; Healthcare Systems; Image; Impaired cognition; In Vitro; Intravenous; Lead; Liver; Mediating; Mentors; Microbubbles; Microcirculation; Modeling; Molecular; Monitor; Mus; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Patients; Penetration; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase I Clinical Trials; Phase II Clinical Trials; Physicians; Physics; Physiology; Pittsburgh Compound-B; Plasma; Positron-Emission Tomography; Proteins; Research Project Grants; Scientist; Signal Transduction; Site; Statistical Data Interpretation; Stress; Structure; Suspensions; Techniques; Testing; Therapeutic; Tight Junctions; Training; Translational Research; Ultrasonic Transducer; Umbilical vein; aging population; bench to bedside; beta-site APP cleaving enzyme 1; blood-brain barrier permeabilization; brain endothelial cell; career; career development; clinical translation; cognitive ability; cognitive function; design; experimental study; human old age (65+); improved; in vivo; inhibitor; insight; meetings; mouse model; multidisciplinary; nervous system disorder; novel therapeutics; side effect; sonoporation; symptom management; theranostics; therapeutic candidate; treatment strategy; ultrasound

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a devastating, progressive, neurodegenerative disease that affects millions of Americans, yet there is no cure, and there are very limited treatment options. Failure of otherwise promising drugs for AD may be due, in part, to poor penetration into the brain and/or large systemic dose requirements to achieve therapeutic brain concentrations, resulting in off-target effects. To address blood brain barrier (BBB) impenetrability, ultrasound-targeted microbubble cavitation (UTMC) is being explored as a new treatment strategy for AD. In this approach, low intensity ultrasound is applied to intravenously injected ultrasound contrast agents (microbubbles) as they traverse the microcirculation of the brain. UTMC causes transient endothelial barrier hyperpermeability, allowing for site-specific delivery of therapeutics across the BBB. While UTMC shows promise as a technique to increase BBB permeability, its underlying mechanisms are incompletely understood, ultimately constraining clinical translation. My overarching goal is that UTMC directed to the brain offers an approach to enhance drug delivery across the BBB for treatment of AD. To facilitate clinical translation of this platform, my proposal will determine mechanisms mediating UTMC-induced BBB hyperpermeability and utilize UTMC for delivering therapeutics directed at Ab plaques in vivo in the following Aims: (1) To identify mechanisms by which UTMC causes transient BBB hyperpermeability. UTMC applied to umbilical vein endothelial cells in vitro has been shown to change cytoskeletal dynamics, leading to inter-endothelial cell gaps, which can increase paracellular permeability, and was associated with Ca2+ influx into cells in contact with, and remote from, cavitating microbubbles. Extending these findings to the BBB, I hypothesize that UTMC-mediated Ca2+ influx disrupts tight and adherens junctions between brain microvascular endothelial cells, and may also lead to Ca2+-mediated changes in adjacent astrocytes. A contact co-culture in vitro transwell model of the BBB will be used to study changes in function and structure (confocal microscopy) of endothelial cells and astrocytes after UTMC. (2) To determine whether UTMC-mediated BBB opening, in combination with drug therapy, will lower Ab plaque burden and improve the therapeutic window. I hypothesize that UTMC-mediated BBB opening will decrease the dose required for a specific drug designed to lower Ab plaque deposition, thereby minimizing off-target effects. The drug will be administered, and UTMC will be applied to the brain in a mouse model of AD. Brain Ab plaques will be quantified by serial brain PET imaging. I have assembled an exceptional multidisciplinary team of mentors and collaborators, along with specific coursework and seminars, to acquire the necessary content expertise in AD biology, ultrasound theranostics, imaging, and murine AD models. Through meetings with my mentors and conducting my experiments, I will acquire experiential lessons in rigorous experimental design, data analysis, and presentation. My comprehensive training plan will prepare me to achieve my career goal of becoming a physician-scientist pursuing bench to bedside translational research.

项目摘要/摘要 阿尔茨海默氏病（AD）是一种毁灭性的，进行性的，神经退行性疾病，影响数百万 美国人，但是没有治愈方法，并且治疗方案非常有限。否则承诺的失败 AD的药物可能部分归因于大脑中的渗透率较差和/或大型全身剂量要求 达到治疗性脑浓度，从而产生脱靶效应。解决血脑屏障（BBB） 无法确定性，超声靶向的微泡水中心（UTMC）正在探索作为一种新处理 广告策略。在这种方法中，低强度超声应用于静脉注射的超声对比度 当药物（微泡）穿越大脑的微循环时。 UTMC导致瞬时内皮 屏障超透明度，可以在整个BBB上进行特定于现场的理论传递。而UTMC显示 有望作为提高BBB渗透性的一种技术，其潜在机制是不完全理解的， 最终限制临床翻译。我的总体目标是指向大脑的UTMC提供了 增强BBB的药物递送以治疗AD的方法。促进此的临床翻译 平台，我的建议将确定介导UTMC诱导的BBB超重性的机制并利用 在以下目的中，用于针对体内AB斑块的疗法的UTMC：（1）识别 UTMC引起瞬时BBB超透度性的机制。 UTMC应用于脐静脉 体外的内皮细胞已显示可改变细胞骨架动力学，导致肾上皮细胞间隙， 这会增加细胞细胞的渗透性，并与Ca2+影响与与接触的细胞的影响相关，并且 远离，陷入微泡。将这些发现扩展到BBB，我假设UTMC介导 Ca2+影响会破坏紧密的脑部微血管内皮细胞之间的粘附连接，也可能 导致CA2+介导的相邻星形胶质细胞变化。 BBB的接触式培养在体外Transwell模型 将用于研究内皮细胞和星形胶质细胞功能和结构（共聚焦显微镜）的变化 UTMC之后。 （2）确定UTMC介导的BBB开放是否与药物治疗结合 将降低AB斑块伯恩并改善治疗窗口。我假设UTMC介导的BBB 开放将减少旨在降低AB斑块沉积的特定药物所需的剂量 最小化脱靶效应。该药物将被施用，UTMC将在小鼠中应用于大脑 AD模型。脑AB斑块将通过串行脑PET成像来量化。我组装了一个例外 多学科的导师和合作者团队以及特定的课程和半手 广告生物学，超声疗法，成像和鼠广告模型的必要内容专业知识。通过 与我的导师会面并进行实验，我将获得严格的专家课程 实验设计，数据分析和演示。我的全面培训计划将为我做好准备 实现自己的职业目标，成为一个身体科学家，追求床头翻译研究。