Blood-Brain Barrier Disruption using Focused Ultrasound in a Large Animal Model

在大型动物模型中使用聚焦超声破坏血脑屏障

• 批准号: 7852751
• 负责人: Nathan J. McDannold
• 金额: $ 89.94万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7852751
• 关键词: Accounting; Address; Aftercare; Animal Model; Animals; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Central Nervous System Diseases; Clinical; Contrast Media; Development; Distant; Drug Carriers; Drug Delivery Systems; Drug usage; Evaluation; Flowcharts; Focused Ultrasound Therapy; Functional Magnetic Resonance Imaging; Goals; Healthcare; Histology; Image; Individual; Location; Macaca mulatta; Magnetic Resonance Imaging; Measures; Medical Imaging; Methods; Microbubbles; Modeling; Mus; Neuraxis; Oryctolagus cuniculus; Pathology; Patients; Pharmaceutical Preparations; Pharmacotherapy; Primates; Procedures; Rattus; Risk; Safety; Structure; System; Techniques; Technology; Testing; Ultrasonography; Work; base; brain size; brain tissue; drug development; focus ultra; research study; safety study; sound

DESCRIPTION (Provided by Applicant): The blood-brain barrier (BBB) normally serves to protect the brain from agents that circulate in the blood. However, it also poses a major limitation to drug delivery and the large majority of drugs cannot be used in the central nervous system (CNS). Current methods to overcome the BBB are invasive, non-targeted, and/or require the development of new drug carriers. We have shown previously that short, low-intensity focused ultrasound bursts combined with a microbubble-based ultrasound contrast agent can result in targeted, temporary BBB disruption. Our prior studies in small animals have shown that this disruption can be achieved safely and that even large molecule agents can be delivered to the brain. This technique potentially could represent a fundamental change in the treatment of CNS disease, creating new opportunities for drug development and allowing new uses of currently available drug therapies. With this technology combined with medical imaging, one could develop truly image-guided drug delivery and achieve a drug concentration precisely tailored to an individual patient's CNS pathology. However, certain effects cannot be adequately measured in small animals with the technique. Reflection and standing wave effects and structures in the ultrasound beam path such as the ventricles and large blood vessels can potentially result in unwanted effects outside of the focal zone, and these risks cannot be evaluated in small animal models such as mice, rats, or rabbits. Before moving confidently to patient treatments with this technology, it is essential that its safety profile be established in an animal brain that can take these effects into account. Furthermore, it is possible that the ultrasound exposures can cause functional deficits, which also are difficult to establish in small animal models. Thus, the aim of this work is to perform a safety study of ultrasound-induced BBB disruption in a primate model. The BBB will be temporarily disrupted in rhesus macaques using a clinical MRI-guided focused ultrasound system, and we will evaluate the effects to the brain using MRI, histology, and functional tests. The purpose of this work will to be to perform a safety study in primates of a method that uses focused ultra- sound bursts and a microbubble agent to temporarily disrupt the blood-brain barrier at targeted locations. As the blood-brain barrier is currently a major limitation to the use of drugs for brain disorders, such a technique could have a major impact on healthcare. These experiments are needed to address potential safety issues with the technique that cannot be determined from small animal models.

描述（由申请人提供）： 血脑屏障（BBB）通常用于保护大脑免受血液循环的药物的侵害。但是，这也对药物递送构成了主要限制，并且绝大多数药物不能用于中枢神经系统（CNS）。克服BBB的当前方法是侵入性的，未靶向的和/或需要开发新药载体的方法。我们先前已经表明，与基于微泡的超声对比剂相结合的短而低强度的超声爆发可能会导致靶向的临时BBB破坏。我们对小动物的先前研究表明，可以安全地实现这种破坏，即使是大分子剂也可以传递到大脑。这项技术可能代表了中枢神经系统疾病治疗的根本变化，为药物开发创造了新的机会，并允许使用当前可用的药物疗法。通过这项技术与医学成像相结合，人们可以开发出真正的图像引导的药物输送，并实现精确量身定制的药物浓度。但是，用该技术在小动物中无法充分测量某些效果。超声梁路径（例如心室和大血管）中的反射和驻波效应和结构可能会导致焦距外部的不良影响，并且在小鼠，大鼠或兔子等小动物模型中无法评估这些风险。在对这项技术的患者治疗充满信心之前，必须在可以考虑这些效果的动物大脑中建立其安全性。此外，超声暴露可能会导致功能缺陷，这在小动物模型中也很难建立。因此，这项工作的目的是对灵长类动物模型中超声引起的BBB破坏进行安全研究。 BBB将使用临床MRI引导聚焦超声系统在恒河猕猴中暂时破坏，我们将使用MRI，组织学和功能测试评估对大脑的影响。这项工作的目的是在一种方法的灵长类动物中进行安全研究，该方法使用聚焦的超声爆发和微泡剂来暂时破坏目标位置的血脑屏障。由于目前，血脑屏障是使用药物用于脑部疾病的主要限制，因此这种技术可能会对医疗保健产生重大影响。需要这些实验来解决无法从小动物模型中确定的技术的潜在安全问题。