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

今天，超过3500万美国人年龄超过65岁。在未来30年内， 可能会增加一倍，使越来越多的人面临神经退行性疾病的风险。 在过去的几十年里，已经开发了许多小分子和大分子产品。 开发用于治疗神经退行性疾病，但成功率参差不齐。给药时 在体内全身性地，血脑屏障（BBB）抑制它们递送到受以下影响的区域： 这些疾病。安全和局部打开血脑屏障已被证明是一个平等的 重大挑战。聚焦超声（FUS），结合微泡，仍然是 唯一可以非侵入性诱导局部BBB开放的技术。在此之前，我们的团队 表明，多巴胺能神经元的神经保护和神经恢复， 在疾病的早期阶段，黑质纹状体通路可以通过超声介导的 药物输送在这项研究中，我们将开发和优化治疗诊断超声系统， 同时在体内诱导和绘制小鼠和灵长类动物的BBB开放。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基因递送在小鼠中诱导神经保护和神经恢复 和NHP用于治疗与早期帕金森病相关的帕金森病模型中的运动症状。 PD阶段集合的多学科团队涵盖所有关键专业领域， 如超声和微泡工程、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，本研究将确定治疗诊断FUS是否可以有更多的 通过在诊断成像扫描仪中实施并足够有效， 用于治疗早期帕金森氏症结合基因传递。

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.