A theranostic system for ultrasound-facilitated blood-brain barrier opening

超声促进血脑屏障开放的治疗诊断系统

• 批准号: 10318649
• 负责人: Elisa E. Konofagou
• 金额: $ 63.14万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318649
• 关键词: 3-Dimensional; Adoption; Affect; Age; Aging; American; Amplifiers; Area; Behavioral; Behavioral Symptoms; Blood - brain barrier anatomy; Brain imaging; Central Nervous System Diseases; Clinic; Clinical; Cognitive; Diagnostic; Diagnostic Imaging; Diffuse; Disease; Drug Delivery Systems; Early treatment; Elements; Engineering; FDA approved; Feasibility Studies; Fluorescence; Focused Ultrasound; Gene Delivery; Human; Image; Link; Magnetic Resonance Imaging; Maps; Mechanics; Mediating; Methodology; Microbubbles; Modeling; Movement Disorders; Mus; Neurodegenerative Disorders; Neuronavigation; Neurosciences; Outcome; Parkinson Disease; Pathway interactions; Patients; Permeability; Persons; Pharmaceutical Preparations; Pharmacology; Physiologic pulse; Positron-Emission Tomography; Primate Diseases; Primates; Risk; Safety; System; Techniques; Testing; Therapeutic Uses; Time; Transducers; Treatment Efficacy; Ultrasonography; behavior test; brain parenchyma; cohort; cranium; delivery vehicle; design; dopaminergic neuron; dosage; effective therapy; efficacy evaluation; falls; human old age (65+); in vivo; indexing; medical specialties; model development; motor control; motor symptom; mouse model; multidisciplinary; neuroprotection; neurorestoration; nigrostriatal pathway; nonhuman primate; parkinsonian model; parkinsonian non-human primate; parkinsonian rodent; pressure; real time monitoring; restoration; safety assessment; safety study; small molecule; success; theranostics; ultrasound

Today, over 35 million Americans are over the age of 65. Within the next 30 years this number is likely to double, putting more and more people at increased risk of neurodegenerative disease. Over the past several decades, numerous small- and large-molecule products have been developed for treatment of neurodegenerative diseases with mixed success. When administered systemically in vivo, the blood-brain barrier (BBB) inhibits their delivery to the regions affected by those diseases. Safe and localized opening of the BBB has been proven to pose an equally significant challenge. Focused Ultrasound (FUS), in conjunction with microbubbles, remains the sole technique that can induce localized BBB opening noninvasively. Previously, our group has demonstrated that neuroprotection and neurorestoration in the dopaminergic neurons in the nigrostriatal pathway at the early stages of disease can be induced through ultrasound-mediated drug delivery. In this study, we will develop and optimize a theranostic ultrasound system that can simultaneously induce and map the BBB opening in mice and primates in vivo. As a secondary objective, we will determine whether this new BBB opening systems are sufficient to induce BBB at sufficient levels to induce neuroprotection and neurorestoration through gene delivery in mice and NHP for the treatment of motor symptoms in Parkinsonian models associated with early- stage PD. The multi-disciplinary team assembled encompasses all critical specialty areas such as ultrasound and microbubble engineering, neuroscience as well as MRI, PET and fluorescence brain imaging, behavioral testing and mouse model development as well as clinical specialty in movement disorders.This study will thus determine whether theranostic FUS can have a more widespread impact by being implemented in diagnostic imaging scanners and efficacious enough for the treatment of early stage Parkinson’s in conjunction with gene delivery.

如今，超过3500万美国人的年龄超过65岁。在接下来的30年中，这个数字是 可能会加倍，使越来越多的人面临神经退行性疾病的风险。 在过去的几十年中，许多小分子和大分子产品 开发用于治疗具有混合成功的神经退行性疾病。管理时 在体内，血脑屏障（BBB）抑制了其向受影响区域的分娩 那些疾病。已证明，BBB的安全局部开放构成了同样的姿势 重大挑战。聚焦超声（FUS）与微泡结合在一起，仍然是 唯一可以诱导局部BBB开放的唯一技术。以前，我们的小组有 证明在多巴胺能神经元中的神经保护和神经抑制 疾病早期阶段的Nigrostriatal途径可以通过超声介导的 药物输送。在这项研究中，我们将开发和优化一个可以 同样，在体内诱导并绘制小鼠的BBB开口和素数。作为次要 目的，我们将确定这种新的BBB开放系统是否足以诱导BBB 在足够的水平下，通过小鼠的基因递送诱导神经保护和神经染色 NHP用于治疗与早期模型相关的帕金森氏症模型中的运动症状 阶段PD。多学科团队组装的团队涵盖了所有关键专业领域，例如 作为超声和微泡工程，神经科学以及MRI，PET和荧光 脑成像，行为测试和小鼠模型开发以及临床专业 运动障碍。因此，这项研究将确定肉毒杆菌是否可以具有更多 通过在诊断成像扫描仪中实施并有效地实现宽度的影响 为了治疗早期帕金森氏症与基因的递送。