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: 10541109
• 负责人: Elisa E. Konofagou
• 金额: $ 59.15万
• 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/10541109
• 关键词: 3-Dimensional; Acceleration; Adoption; Affect; Age; Aging; American; Amplifiers; Area; Behavioral; Behavioral Symptoms; Blood - brain barrier anatomy; Brain imaging; Central Nervous System Diseases; Cephalic; Clinic; Clinical; Cognitive; Dedications; 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; Physiologic pulse; Positron-Emission Tomography; Primate Diseases; Primates; Research; Risk; Safety; System; Techniques; Testing; Therapeutic Uses; Time; Transducers; Treatment Efficacy; Ultrasonography; behavior test; blood-brain barrier crossing; brain parenchyma; cohort; cranium; delivery vehicle; design; dopaminergic neuron; dosage; effective therapy; efficacy evaluation; falls; human old age (65+); improved; 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; pharmacologic; 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 万美国人年龄在 65 岁以上。在未来 30 年内，这个数字将 可能会增加一倍，使越来越多的人患神经退行性疾病的风险增加。 在过去的几十年里，无数的小分子和大分子产品被开发出来。 为治疗神经退行性疾病而开发，取得了不同程度的成功。给药时 在体内系统性地，血脑屏障（BBB）抑制它们输送到受感染影响的区域。 那些疾病。事实证明，BBB 的安全和局部打开具有同等的效果。 重大挑战。聚焦超声 (FUS) 与微泡相结合，仍然是 唯一可以非侵入性诱导局部 BBB 打开的技术。此前，我们组曾 证明多巴胺能神经元的神经保护和神经恢复 疾病早期阶段的黑质纹状体通路可以通过超声介导来诱导 药物输送。在这项研究中，我们将开发和优化一种治疗诊断超声系统，该系统可以 同时诱导并绘制小鼠和灵长类动物体内 BBB 开口的图谱。作为二次元 目标，我们将确定这个新的 BBB 打开系统是否足以诱发 BBB 在足够的水平上通过基因传递诱导小鼠神经保护和神经恢复 和 NHP 用于治疗与早期相关的帕金森病模型中的运动症状 PD 阶段。组建的多学科团队涵盖所有关键专业领域，例如 如超声波和微泡工程、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，这项研究将确定治疗诊断 FUS 是否可以有更多的效果 通过在诊断成像扫描仪中实施而产生广泛影响并且足够有效 用于与基因递送结合治疗早期帕金森病。