Pathfinder: An experimental medicine study of the 18 kD translocator protein as a novel neuroimmunodulatory target for multiple sclerosis

探路者：18 kD 易位蛋白作为多发性硬化症新型神经免疫调节靶点的实验医学研究

• 批准号: MR/N026934/1
• 负责人: Paul Matthews
• 金额: $ 115.25万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN026934%2F1
• 关键词: Pathfinder; experimental; medicine; study; 18

Multiple sclerosis (MS) involves inflammation in the brain caused by lymphocytes that that circulate in the blood, by macrophages derived from another set of blood cells and by microglia, which are the brain's own resident inflammatory cells. Although treatments developed to date have focused on better controlling lymphocyte activity, microglia (and macrophages, which share some key features of microglia) also play a major role in the inflammation associated with relapses. They also may be important in driving the neurodegeneration associated with progressive forms of the disease. Our group has discovered, for example, that disability in secondary progressive MS is greater in people with higher levels of microglial activation in the brain. However, activated microglia are not directly modulated by current approved medicines for MS. The "18kD Translator Protein" or "TSPO" is a natural molecule richly expressed in microglia and macrophages. Studies by many scientists using cells in a dish or animal models of diseases suggest that chemicals (e.g., some related to common anti-anxiety drugs like valium) binding to TSPO reduce inflammation. This suggests that TSPO may provide a new way of modulating inflammation associated with MS and, as molecules developed to interact with TSPO all can penetrate the brain, have a unique action on microglia. This possibility has never been tested in human studies.To address this, we are proposing a comprehensive series of experiments in humans and with human cells or tissue that are intended to evaluate TSPO as a novel immune modulatory target for treatment of people with MS. We are focusing on secondary progressive MS because it is a serious, progressive form of the disease associated with high levels of brain microglial activation that cannot be well treated with current approved medicines. Our study will involve studies of brain tissue (donated to the MS Society Brain Bank by people with MS) to see whether TSPO is increased in microglia that are producing the kinds of chemical signals that damage nerve cells and myelin. We will study the inflammatory responses of human microglia grown in a dish when they are treated with molecules that modulate TSPO functions. Finally, under very carefully controlled conditions, we will administer the safe TSPO binding molecule XBD173 to healthy volunteers and to people with MS daily for a week to understand whether immune responses really can be changed with administration of this kind of molecule. Multiple measures of inflammation in the blood and in the brain will be used. Relatively new magnetic resonance imaging (MRI) and positron emission tomography (PET) brain scanning methods will be further validated for this application and then used as an additional tool in the healthy volunteers and people with MS to provide information more directly about the effects on brain inflammation.Our interdisciplinary clinical study will bring together a broad range of experts in drug development for MS, neuroimmunology and neuroimaging. It will provide a first test of the hypothesis that a TSPO binding molecule can modulate the inflammatory responses of microglia in humans, help us to discover how to monitor any effects that such molecules might be having and begin to tell us how they work. We do not believe that XBD173 itself can be used as a treatment, but many other molecules have been developed that should work in a similar way. If our study is successful, we intend to select and further develop one of these other molecules for use as a potential combination treatment with more traditional MS drugs. Together, a molecule modulating microglia and one of the currently approved disease modifying drugs that has a major effect on lymphocytes could provide a more powerful way of treating not just relapses, but also the progressive forms of MS.

多发性硬化症（MS）涉及由血液中循环的淋巴细胞、来自另一组血细胞的巨噬细胞和小胶质细胞引起的大脑炎症，小胶质细胞是大脑自身的常驻炎症细胞。尽管迄今为止开发的治疗方法主要集中在更好地控制淋巴细胞活性，但小胶质细胞（和巨噬细胞，它们具有小胶质细胞的一些关键特征）也在与复发相关的炎症中发挥重要作用。它们也可能在驱动与疾病进展形式相关的神经变性方面很重要。例如，我们的研究小组发现，在大脑中小胶质细胞激活水平较高的人群中，继发性进展性MS的残疾程度更高。然而，激活的小胶质细胞不直接由目前批准的MS药物调节。“18kD翻译蛋白”或“TSP0”是在小胶质细胞和巨噬细胞中丰富表达的天然分子。许多科学家使用培养皿中的细胞或疾病的动物模型进行的研究表明，化学物质（例如，一些与普通抗焦虑药物如安定有关）与TSPO结合减少炎症。这表明TSPO可能提供了一种调节与MS相关的炎症的新方法，并且由于开发用于与TSPO相互作用的分子都可以穿透大脑，因此对小胶质细胞具有独特的作用。这种可能性从未在人体研究中进行过测试。为了解决这个问题，我们提出了一系列全面的人体实验和人体细胞或组织实验，旨在评估TSPO作为治疗MS患者的新型免疫调节靶点。我们专注于继发性进展性MS，因为它是一种严重的，这种疾病的进展形式与高水平的脑小胶质细胞活化有关，目前批准的药物无法很好地治疗。我们的研究将涉及对脑组织的研究（由MS患者捐赠给MS协会脑库），以了解TSPO是否在产生损害神经细胞和髓鞘的化学信号的小胶质细胞中增加。我们将研究在培养皿中生长的人类小胶质细胞在接受调节TSPO功能的分子处理时的炎症反应。最后，在非常仔细控制的条件下，我们将每天向健康志愿者和MS患者施用安全的TSPO结合分子XBD 173，持续一周，以了解施用这种分子是否真的可以改变免疫反应。将使用血液和大脑中炎症的多种测量方法。相对较新的磁共振成像（MRI）和正电子发射断层扫描（PET）脑扫描方法将进一步验证这一应用，然后在健康志愿者和MS患者中用作额外的工具，以更直接地提供有关脑炎症影响的信息。我们的跨学科临床研究将汇集广泛的MS药物开发，神经免疫学和神经影像学专家。它将提供TSPO结合分子可以调节人类小胶质细胞炎症反应的假设的第一个测试，帮助我们发现如何监测这些分子可能具有的任何影响，并开始告诉我们它们是如何工作的。我们不认为XBD 173本身可以用作治疗，但已经开发了许多其他分子，它们应该以类似的方式发挥作用。如果我们的研究成功，我们打算选择并进一步开发这些其他分子之一，作为与更传统的MS药物的潜在联合治疗。总之，一种调节小胶质细胞的分子和一种目前批准的对淋巴细胞有重大影响的疾病修饰药物可以提供一种更强大的治疗方法，不仅可以治疗复发，还可以治疗MS的进行性形式。

项目成果

Alzheimer's disease-related transcriptional sex differences in myeloid cells.

• DOI: 10.1186/s12974-022-02604-w
• 发表时间: 2022-10-05
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3

OPTIMISE: MS study protocol: a pragmatic, prospective observational study to address the need for, and challenges with, real world pharmacovigilance in multiple sclerosis.

• DOI: 10.1136/bmjopen-2021-050176
• 发表时间: 2021-11-25
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Dobson R;Craner M;Waddingham E;Miller A;Cavey A;Webb S;Hemingway C;Hobart J;Evangelou N;Scolding N;Rog D;Nicholas R;Marta M;Blain C;Young CA;Ford HL;Matthews PM
• 通讯作者: Matthews PM

Translocator positron-emission tomography and magnetic resonance spectroscopic imaging of brain glial cell activation in multiple sclerosis.

• DOI: 10.1177/1352458516681504
• 发表时间: 2017-10
• 期刊: Multiple sclerosis (Houndmills, Basingstoke, England)
• 作者: Datta G;Violante IR;Scott G;Zimmerman K;Santos-Ribeiro A;Rabiner EA;Gunn RN;Malik O;Ciccarelli O;Nicholas R;Matthews PM
• 通讯作者: Matthews PM