Optimization of ultrasound-facilitated blood-brain barrier opening

描述(申请人提供)：超过400万美国男性和女性患有阿尔茨海默氏症；100万人患有帕金森氏症；35万人患有多发性硬化症；2万人来自 淀粉样侧索硬化症(ALS)。在全球范围内，这四种疾病的患者超过2000万人。尽管近年来在认识这些疾病方面取得了很大进展，但由于血脑屏障(BBB)的不通透性，目前几乎没有有效的治疗方法和治疗方法。血脑屏障(BBB)的安全和局部开放已被证明是脑部给药的一个重大挑战。在被证明有效的破坏血脑屏障的方法中，聚焦超声(FUS)结合微泡是唯一一种可以无创和局部地诱导局部血脑屏障开放的技术。这项研究的基本假设是，通过控制超声和微泡参数，可以成功地预测和操纵FUS诱导的BBB开放的程度和可逆性，从而有效地传递跨BBB。本研究的主要目的是阐明超声、微泡和局部微环境在FUS开放血脑屏障过程中的相互作用。此外，体内血脑屏障开放的机制将通过使用附着在微泡外壳上的磁共振造影剂进行监测，这将允许观察治疗后外壳材料的位置和堆积。组建的团队涵盖了所需的所有重要专业领域，如超声波和微气泡工程以及磁共振和荧光脑成像。这项研究的具体目的是：1)设计和确定可逆和局部BBB开放的微泡特征；2)确定不同微泡下BBB开放的机制和体内超声参数；3)利用磁共振和荧光成像对BBB开放进行定量分析；以及4)成像BBB开放和体内反式BBB传递的机制。通过实现拟议研究的目标，FUS程序的机制将得到更彻底的理解，FUS诱导的BBB开放将得到优化，以便有选择地和准确地将药理药物输送到目前无法治疗的大脑区域。 公共卫生相关声明(由申请者提供)：由于血脑屏障(BBB)的非渗透性，神经疾病和所有与年龄相关的神经退行性疾病仍然无法治疗，尽管有数千种药理药物可用。本研究的目的是阐明超声、微泡和局部微环境之间的相互作用。 BBB以FUS开场。

DESCRIPTION (provided by applicant): Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amythrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available mainly due to the impermeability of the blood-brain barrier (BBB). Safe and localized opening of the blood-brain barrier (BBB) has been proven to present a significant challenge in brain drug delivery. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. The underlying hypothesis of this study is that, through control over the ultrasound and microbubble parameters, the extent and reversibility of the BBB opening induced by FUS can be successfully predicted and manipulated for efficient trans-BBB delivery. The primary objective of this study is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS. In addition, the mechanism of the BBB opening in vivo will be monitored by the use of an MR contrast agent attached to the microbubble shell, which will allow observation of the location and accumulation of the shell material following treatment. The team assembled encompasses all important specialty areas required, such as ultrasound and microbubble engineering as well as MR and fluorescence brain imaging. The specific aims of the study are to: 1) engineer and determine the microbubble characteristics for a reversible and localized BBB opening; 2) identify the mechanism of BBB opening at distinct microbubble and ultrasound parameters in vivo; 3) perform quantitative analysis of the BBB opening using MR and fluorescence imaging; and 4) image the mechanism of BBB opening and trans-BBB delivery in vivo. By achieving the goals of the proposed study, the mechanism of the FUS procedure will be more thoroughly understood and the FUS-induced BBB opening will be optimized for selectively and precisely delivering pharmacological agents to currently untreatable brain regions. Public Health Relevance Statement (provided by applicant): Due to the impermeability of the blood-brain barrier (BBB), neurological disorders and all age-related neurodegenerative diseases remain untreatable despite the thousands of pharmacological agents available. The objective of this study is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS.