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

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中循环的药物的影响。然而，它也对药物传递构成了主要限制，而且绝大多数药物不能在中枢神经系统(CNS)使用。目前克服血脑屏障的方法是侵入性的、非靶向性的和/或需要开发新的药物载体。我们以前已经证明，短时间、低强度聚焦超声脉冲与基于微泡的超声造影剂相结合可以导致靶向的、暂时的血脑屏障破坏。我们之前在小动物身上的研究表明，这种干扰可以安全地实现，甚至大分子制剂也可以被输送到大脑。这项技术可能代表着中枢神经系统疾病治疗的根本性变化，为药物开发创造新的机会，并允许现有药物疗法的新用途。利用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药物输送，并实现精确地针对单个患者的中枢神经系统病理定制的药物浓度。然而，使用这项技术无法在小动物身上充分测量某些影响。反射和驻波效应以及超声波束路径中的结构(如脑室和大血管)可能会在焦点区域之外导致不必要的影响，并且这些风险无法在小鼠、大鼠或兔子等小动物模型中进行评估。在信心十足地使用这项技术进行患者治疗之前，至关重要的是，在动物大脑中建立起它的安全概况，可以考虑到这些影响。此外，超声波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，这项工作的目的是在灵长类动物模型中进行超声诱导的血脑屏障破坏的安全性研究。使用临床MRI引导的聚焦超声系统，恒河猴的血脑屏障将暂时被破坏，我们将使用MRI、组织学和功能测试来评估对大脑的影响。这项工作的目的是在灵长类动物中进行一项安全性研究，研究一种使用聚焦超音波和微气泡剂暂时破坏目标位置血脑屏障的方法。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素，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这项技术的潜在安全问题，而这项技术无法从小动物模型中确定。

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.