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: 7940881
• 负责人: Nathan J. McDannold
• 金额: $ 89.81万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7940881
• 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（申请人提供）： 血脑屏障（BBB）通常用于保护大脑免受血液中循环的药剂的影响。然而，它也对药物递送造成了重大限制，并且绝大多数药物不能用于中枢神经系统（CNS）。目前克服BBB的方法是侵入性的、非靶向的和/或需要开发新的药物载体。我们以前已经证明，短的，低强度的聚焦超声脉冲群结合微泡超声造影剂可以导致有针对性的，暂时的BBB中断。我们之前在小动物中的研究表明，这种破坏可以安全地实现，甚至可以将大分子药物输送到大脑。这项技术可能代表CNS疾病治疗的根本性变化，为药物开发创造新的机会，并允许目前可用的药物疗法的新用途。通过将该技术与医学成像相结合，可以开发真正的图像引导药物递送，并实现针对个体患者CNS病理学精确定制的药物浓度。然而，使用该技术无法在小动物中充分测量某些影响。超声束路径中的反射和驻波效应和结构（如心室和大血管）可能会导致聚焦区以外的不良效应，并且无法在小动物模型（如小鼠、大鼠或家兔）中评价这些风险。在使用这项技术自信地进行患者治疗之前，必须在动物大脑中建立其安全性，以考虑这些影响。此外，超声波暴露可能会导致功能缺陷，这也很难在小动物模型中建立。因此，这项工作的目的是在灵长类动物模型中进行超声诱导BBB破坏的安全性研究。将使用临床MRI引导的聚焦超声系统暂时破坏恒河猴的BBB，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灵长类动物中进行一项安全性研究，该研究使用聚焦超声爆破和微泡剂暂时破坏目标位置的血脑屏障。由于血脑屏障目前是使用药物治疗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该技术的潜在安全问题，这些问题无法从小动物模型中确定。