Focused ultrasound therapy for remitting the symptoms of MS in a rat model

项目摘要 多发性硬化（MS）是一种免疫介导的中枢神经系统（CNS）疾病， 治疗选择对于减缓最终的疾病进展仅适度有效。美国已 在成人中大约有500，000例MS病例，在全世界大约有250万例成人MS病例， 女士这种疾病最初涉及免疫介导的脱髓鞘和CNS内轴突的横断， 随后转变为与神经营养支持不足相关的神经退行性疾病， CNS。认知和行走障碍在60-80%以上的MS患者中很常见， 失业、残疾和生活质量受损的因素。这些问题强调了 开发新的治疗方案，以减轻和降低MS的严重程度。 通过免疫抑制剂的免疫疗法已经成为用于缓解免疫缺陷的标准护理。 MS的慢性复发形式。这些药物中的许多通过将淋巴细胞隔离到淋巴结来起作用， 从而减少循环的白色血细胞的数量，导致更少的细胞可用于攻击 神经纤维所有可用的免疫治疗剂都具有与抑制免疫应答相关的副作用。 免疫系统与最关键的包括血压升高，肝脏问题和死亡。 基于淋巴细胞减少可以减轻MS症状的想法，我们提出了一种新的治疗方法。 使用聚焦的用于靶向驻留在颈部淋巴结（CLN）中的淋巴细胞的治疗性干预 超声在实验性自身免疫性脑脊髓炎（EAE）大鼠MS模型中的应用 允许热疗靶向特定组织，即，主要为CNS服务的CLN， 降解或杀死驻留在CLN中的淋巴细胞。通过杀死或降低淋巴细胞的功能， CLN，我们假设EAE的严重程度将减轻。我们最近的试点研究首次提供了 有证据表明，这种方法导致EAE症状的缓解在统计学上显著高于没有 疗法然而，我们的初步研究是在有限数量的动物上进行的，只有一次暴露条件。到 为了进一步验证我们的假设并证明这种新型EAE治疗的有效性，需要进行更大规模的研究 探索一系列治疗暴露条件，较大动物数量检测较小影响， 分析以阐明治疗效果的机制并量化副作用。 为了满足这些需要，提出了两个具体目标。第一个具体目标是探索一系列 超声治疗暴露条件并量化暴露条件对治疗的影响 结果。待探索的暴露条件范围包括：热剂量、治疗之间的时间 和EAE注射剂量/治疗反应。第二个具体目标是阐明治疗对 易受上呼吸道病毒感染。我们将量化任何免疫反应的降低 这是我们FUS疗法的副作用

Project Summary Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS) and existing treatment options are only modestly effective for slowing eventual disease progression. The United States has approximately 500,000 cases of MS in adults and worldwide there are approximately 2.5 million cases of adult MS. This disease initially involves immune-mediated demyelination and transection of axons within the CNS, and later transitions into a neurodegenerative condition associated with insufficient neurotrophic support in the CNS. Cognitive and walking impairments are common in upwards of 60-80% of persons with MS, and are risk factors for unemployment, disability, and compromised quality of life. These issues underscore the importance of developing new therapy regimens to mitigate and reduce the severity of MS. Immunotherapy through immunosuppressive agents has been the standard of care used to alleviate chronic relapse forms of MS. Many of these drugs work by sequestering lymphocytes to the lymph nodes, thereby reducing the number of circulating white blood cells resulting in fewer cells available to attack the nerve fibers. All of the available immunotherapy agents have side effects associated with the suppression of the immune system with the most critical including increased blood pressure, liver problems and death. Based on the idea that a reduction of lymphocytes can alleviate symptoms of MS, we propose a novel therapeutic intervention for targeting lymphocytes residing in the cervical lymph nodes (CLNs) using focused ultrasound in the experimental autoimmune encephalomyelitis (EAE) rat model of MS. Focused ultrasound allows hyperthermia to be targeted to specific tissues, i.e., the CLNs which primarily service the CNS, to degrade or kill lymphocytes residing in the CLNs. By killing or degrading the function of lymphocytes in the CLNs, we hypothesize that the severity of EAE will be alleviated. Our recent pilot study has provided first ever evidence that this approach results in remittance of EAE symptoms statistically significantly more than without therapy. However, our pilot study was on a limited number of animals with a single exposure condition. To further test our hypothesis and demonstrate the efficacy of this novel EAE therapy, a larger study is warranted to explore a range of therapy exposure conditions, larger animal numbers to detect smaller effects and analyses to elucidate mechanisms responsible for the therapy effects and quantify side effects. To address these needs, two specific aims are proposed. The first specific aim is to explore a range of ultrasound therapy exposure conditions and quantify the effects of the exposure conditions on the therapy outcomes. The range of exposure conditions to be explored include: thermal dose, timing between treatments and EAE injection dose/treatment response. The second specific aim is to elucidate the effects of treatment on susceptibility to an upper-respiratory viral infection. We will quantify any reduction in immune response resulting as a side effect from our FUS therapy.