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Enhancing antibody delivery across the blood brain barrier as a therapeutic

增强抗体穿过血脑屏障的递送作为治疗方法

基本信息

批准号：
1789264
负责人：
金额：
--
依托单位：
University of Southampton
依托单位国家：
英国
项目类别：
Studentship
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=studentship-1789264
关键词：
Enhancing antibody delivery across blood

项目摘要

Dementia, including its most common form, Alzheimers disease, has become a major public health issue with 44 million people affected world-wide. New insights in disease pathways have discovered a hard-wired link between the brain and our immune system which is activated following danger signals such as infection, or stress. Under healthy conditions, this immune-to-brain signalling results in transient activation of physiological, metabolic and neuroendocrine pathways that aid our recovery. However, this signalling is not always harmless; elderly or individuals with ongoing CNS diseases show exaggerated responses to these dangers signals as a result of structural and/or functional changes to the brain, making this communication maladaptive. The underlying biological mechanisms of accelerated neuropathology following systemic infection are incompletely understood, but a role for microglia has been suggested from a range of experimental studies, including our studies performed in Southampton. These innate immune cells of the brain become primed in aging and CNS disease and exhibit a lower threshold for activation and following systemic infection these cells secrete increased levels of IL-1b and TNFa in the brain, which is detrimental for neuronal function. These observations have led to the identification of novel therapeutic targets for treatment of Alzheimers disease and thus have clear clinical relevance. For example, cognitive decline in patients with elevated levels of circulating cytokines progress faster when compared to patients with low levels of these pro-inflammatory biomarkers. More importantly, in a small Phase I/II safety study the cognitive decline and other behavioural changes was not as marked as the placebo group following administration of a TNF-a inhibitor (Etanercept), suggesting that blocking this inflammatory immune signal may be beneficial and delay onset of dementia. The BBB is a major obstacle to the delivery of therapeutic antibodies at effective doses to the CNS. Development of disease modifying drugs for neurodegenerative diseases is urgently needed, and recent in vitro and preclinical studies have pursued transporter proteins expressed on the luminal side of the BBB to shuttle large molecular cargos across the BBB. Medimmune has generated a novel technology that increases BBB influx of large biologics up to 10 percent, outperforming technologies from their competitors. Inthis studentship we aim to test for the first time if this new technology can be applied to models of systemic infection/inflammation and neurodegeneration, which is increasingly recognised as an important risk factors for developing dementia, caused by Alzheimers diseases or vascular dementia.

痴呆症，包括其最常见的形式，阿尔茨海默病，已成为一个主要的公共卫生问题，全球有4400万人受到影响。对疾病通路的新见解发现了大脑和我们的免疫系统之间的一种硬连线联系，这种联系在感染或压力等危险信号后被激活。在健康的条件下，这种免疫到大脑的信号传导导致生理，代谢和神经内分泌途径的短暂激活，有助于我们的恢复。然而，这种信号并不总是无害的;老年人或患有持续CNS疾病的个体由于大脑的结构和/或功能变化而对这些危险信号表现出过度的反应，使得这种交流不适应。全身感染后神经病理学加速的潜在生物学机制尚不完全清楚，但小胶质细胞的作用已从一系列实验研究中提出，包括我们在南安普顿进行的研究。大脑的这些先天性免疫细胞在衰老和CNS疾病中被激发，并表现出较低的激活阈值，并且在全身感染后，这些细胞在大脑中分泌增加水平的IL-1b和TNF α，这对神经元功能是有害的。这些观察结果导致了用于治疗阿尔茨海默病的新的治疗靶点的鉴定，因此具有明确的临床相关性。例如，与这些促炎生物标志物水平低的患者相比，循环细胞因子水平升高的患者的认知下降进展更快。更重要的是，在一项小型I/II期安全性研究中，在给予TNF-α抑制剂（依那西普）后，认知下降和其他行为变化不如安慰剂组显著，这表明阻断这种炎症免疫信号可能是有益的，并延迟痴呆的发作。BBB是将治疗性抗体以有效剂量递送至CNS的主要障碍。迫切需要开发用于神经退行性疾病的疾病修饰药物，并且最近的体外和临床前研究已经追求在BBB的腔侧上表达的转运蛋白以穿梭大分子货物穿过BBB。Medimmune开发了一种新技术，可将大生物制剂的BBB流入量提高10%，优于竞争对手的技术。在这个学生项目中，我们的目标是首次测试这种新技术是否可以应用于全身感染/炎症和神经退行性疾病的模型，这越来越被认为是由阿尔茨海默病或血管性痴呆引起的痴呆症的重要风险因素。