Ultrasound-Mediated Blood-Brain Barrier Permeabilization in Primates

描述（由申请人提供）：血脑屏障（BBB）既是防止生理有害物质渗透到中枢神经系统（CMS）的保障，也是治疗药物递送的一个相当大的障碍。一项允许安全、靶向、可逆地打开血脑屏障的技术可能会彻底改变中枢神经系统疾病的研究和治疗，包括神经退行性疾病、脑和脊髓恶性肿瘤，这些疾病已被证明对传统方法有抵抗力。高渗溶液破坏血脑屏障增强了大分子对中枢神经系统的渗透，但代价是明显的流体转移和缺乏区域特异性。超声介导的血脑屏障破坏是另一种探索方法。高强度聚焦超声（HIFU）已被证明可以在不导致细胞损伤的能量水平上打开血脑屏障，但相关的骨和邻近组织的加热阻碍了HIFU的应用，而不直接暴露于大脑，从而产生骨窗。另一个缺点是诱导打开的持续时间长。最近，低强度定向超声（LODUS）已被证明对大脑微血管的屏障特性具有类似的效果，而没有HIFU的混淆。当非侵入性经颅LODUS应用于人类患者时，发现MRI造影剂外渗增强而无损伤证据，偶然发现了透性作用。随后的啮齿动物研究表明，即使在非优化条件下，LODUS也能诱导血脑屏障对腺病毒载体等物质形成安全、快速可逆的开放。这项I期研究的目标是进行剂量反应实验，解决重要的超声传递参数强度和脉冲长度，在非洲绿猴的安全性和有效性的临床前验证。由于重要的解剖学考虑，拟议的实验不可能在非灵长类动物模型中进行，也不可能在人类中进行，因为成本和伦理原因。Evans Blue与血清白蛋白结合，将被用作大分子血脑屏障通透性的标记物，从而通过成熟的荧光技术实现视觉和定量的疗效测定。这些灵长类动物优化研究的成功完成将为脑屏障可逆开放的研究和治疗应用提供可靠的和临床相关的方案，用于神经退行性疾病、脑癌和其他中枢神经系统疾病。大脑中的血管与身体其他部位的血管不同，因为它们可以阻止大多数药物进入周围组织。虽然这通常是有益的，但它可能会抑制可用于成功治疗阿尔茨海默氏症和脑癌等疾病的治疗方法的范围。这项研究旨在开发一种将药物和其他治疗方法以一种安全且易于应用的方式输送到大脑的方法。

DESCRIPTION (provided by applicant): The blood-brain barrier (BBB) represents both a safeguard against the penetration of physiologically harmful substances into the central nervous system (CMS), and a considerable hurdle to the delivery of therapeutic agents. A technology allowing safe, targeted, reversible opening of the BBB would potentially revolutionize both the study and treatment of CNS disorders, including neurodegenerative conditions and brain and spinal cord malignancies that have proven resistant to conventional approaches. BBB disruption with hypertonic solutions enhances CNS penetration of macromolecules, but at the cost of pronounced fluid shifts and lack of regional specificity. Ultrasound-mediated BBB disruption has been another approach explored. High intensity focused ultrasound (HIFU) has been demonstrated to open the BBB at energy levels that do not result in cellular injury, but associated heating of bone and adjacent tissue prevents HIFU application without direct exposure of the brain by the creation of a bone window. A further drawback is the long duration of opening induced. More recently, low intensity directed ultrasound (LODUS) has been demonstrated to have a similar effect on the barrier properties of the cerebral microvasculature without the confounds of HIFU. Incidental discovery of the permeabilizing effect occurred when non-invasive transcranial application of LODUS to a human patient was found to result in enhanced extravasation of MRI contrast material without evidence of injury. Subsequent rodent studies demonstrated that even under non- optimized conditions LODUS induced a safe and rapidly reversible opening of the BBB to substances as large as adenovirus vectors. The goal of this Phase I study will be to conduct dose response experiments addressing the important ultrasound delivery parameters of intensity and pulse length in a preclinical validation of safety and efficacy in African green monkeys. The proposed experiments would not be possible in non-primate animal models for important anatomic considerations or in humans for cost and ethical reasons. Evans Blue, which binds serum albumin, will be employed as a marker of macromolecule BBB permeability to allow both a visual and quantitative determination of efficacy through well established fluorometric techniques. Successful completion of these primate optimization studies will allow development of robust and clinically relevant protocols for the reversible opening of the BBB for research and therapeutic applications to neurodegenerative diseases, brain cancer and other CNS conditions. Blood vessels in the brain differ from those in the rest of the body in that they prevent most drugs from passing into the surrounding tissue. While this is often beneficial, it can inhibit the range of therapies that can be employed to successfully treat diseases such as Alzheimer's and brain cancer. This research aims to develop a method to deliver drugs and other therapies to the brain in a way that is safe and easy to apply.