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

聚焦超声疗法可缓解大鼠模型中的多发性硬化症症状

• 批准号: 9454946
• 负责人: Michael L. Oelze
• 金额: $ 22.91万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9454946
• 关键词: Address; Adopted; Adrenal Cortex Hormones; Adult; Adverse effects; Aftercare; Animal Model; Animals; Articular Range of Motion; Axon; Biological Assay; Blood Circulation; Blood Pressure; Cause of Death; Cells; Central Nervous System Diseases; Cervical lymph node group; Cessation of life; Chronic; Clinical; Cognitive; Demyelinations; Deterioration; Disease; Disease Progression; Dose; Experimental Autoimmune Encephalomyelitis; Fall prevention; Focused Ultrasound; Focused Ultrasound Therapy; High Prevalence; Histologic; Hyperthermia; Immune; Immune System Diseases; Immune System and Related Disorders; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Impairment; Inflammatory Response; Injection of therapeutic agent; Leukocytes; Liver; Lymphocyte; Lymphocyte Function; Mediating; Medical; Modeling; Multiple Sclerosis; Multiple Sclerosis Lesions; Nerve Degeneration; Nerve Fibers; Neuraxis; Pathology; Persons; Pharmaceutical Preparations; Pharmacotherapy; Physical therapy; Pilot Projects; Placebos; Population; Predisposition; Quality of life; Rat Coronavirus; Rattus; Regimen; Relapse; Remittance; Risk Factors; Services; Severities; Spasm; Stretching; Superficial Cervical Lymph Node; Symptoms; Testing; Therapeutic Effect; Time; Tissues; Ultrasonic Therapy; Unemployment; United States; Viral Respiratory Tract Infection; Walking; Weight; Work; base; body system; disability; gray matter; immunoregulation; improved; killings; lymph nodes; multiple sclerosis treatment; novel; novel therapeutic intervention; novel therapeutics; prevent; reduce symptoms; response; standard of care; strength training; success; therapeutic evaluation; therapy outcome; treatment effect; treatment response; white matter

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.

项目概要 多发性硬化症（MS）是一种免疫介导的中枢神经系统（CNS）疾病，现有的 治疗方案对于减缓最终疾病进展的效果有限。美国有 大约有 500,000 例成人多发性硬化症病例，全世界大约有 250 万例成人多发性硬化症病例 多发性硬化症。这种疾病最初涉及中枢神经系统内免疫介导的脱髓鞘和轴突横断， 然后转变为与神经营养支持不足相关的神经退行性疾病 中枢神经系统。认知和行走障碍在 60-80% 的多发性硬化症患者中很常见，并且存在风险 失业、残疾和生活质量下降的因素。这些问题凸显了重要性 开发新的治疗方案以减轻和降低多发性硬化症的严重程度。 通过免疫抑制剂进行的免疫治疗已成为缓解病情的标准治疗方法 MS 的慢性复发形式。许多这些药物通过将淋巴细胞隔离到淋巴结来发挥作用， 从而减少循环白细胞的数量，导致可攻击的细胞减少 神经纤维。所有可用的免疫治疗药物都有与抑制相关的副作用 最关键的免疫系统包括血压升高、肝脏问题和死亡。 基于减少淋巴细胞可以缓解多发性硬化症症状的想法，我们提出了一种新的方法 使用聚焦疗法针对颈淋巴结（CLN）中的淋巴细胞进行治疗干预 超声在 MS 实验性自身免疫性脑脊髓炎 (EAE) 大鼠模型中的应用。聚焦超声 允许热疗针对特定组织，即主要服务于中枢神经系统的 CLN， 降解或杀死 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 的严重程度将会减轻。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 症状缓解的效果在统计学上显着高于不采用这种方法的情况 治疗。然而，我们的试点研究是针对数量有限的具有单一暴露条件的动物。到 进一步检验我们的假设并证明这种新型 EAE 疗法的功效，需要进行更大规模的研究 探索一系列治疗暴露条件、更大的动物数量以检测更小的影响以及 分析以阐明治疗效果的机制并量化副作用。 为了满足这些需求，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、治疗之间的时间安排 和 EAE 注射剂量/治疗反应。第二个具体目标是阐明治疗对患者的影响 对上呼吸道病毒感染的易感性。我们将量化免疫反应的任何减少 这是我们 FUS 疗法的副作用。