Enhancing antibody delivery across the blood brain barrier as a therapeutic

痴呆症，包括其最常见的形式阿尔茨海默病，已成为一个重大的公共卫生问题，全世界有4 400万人受到影响。对疾病途径的新见解发现，大脑和免疫系统之间存在着一种固有的联系，当感染或压力等危险信号出现时，免疫系统就会被激活。在健康状况下，这种免疫到大脑的信号导致生理、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；由于大脑结构和/或功能的改变，老年人或患有持续性中枢神经系统疾病的个体对这些危险信号表现出夸大的反应，使这种交流不适应。全身性感染后神经病理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得到建议，包括我们在南安普顿进行的研究。大脑的这些先天免疫细胞在衰老和中枢神经系统疾病中被激活，表现出较低的激活阈值，在全身感染后，这些细胞在大脑中分泌增加的IL-1b和TNFa水平，这对神经元功能是有害的。这些观察结果导致了阿尔茨海默病治疗的新治疗靶点的确定，因此具有明确的临床意义。例如，与这些促炎生物标志物水平较低的患者相比，循环细胞因子水平升高的患者的认知能力下降进展得更快。更重要的是，在一项小型I/II期安全性研究中，在给予TNF-a抑制剂（依那西普）后，认知能力下降和其他行为变化没有安慰剂组那么明显，这表明阻断这种炎症免疫信号可能是有益的，可以延缓痴呆症的发作。血脑屏障是向中枢神经系统递送有效剂量的治疗性抗体的主要障碍。开发用于神经退行性疾病的疾病修饰药物是迫切需要的，最近的体外和临床前研究已经开始寻求在血脑屏障管腔侧表达的转运蛋白，以将大分子货物穿过血脑屏障。Medimmune开发了一种新技术，可以将大型生物制剂的BBB流入增加10%，超过竞争对手的技术。在这项研究中，我们的目标是首次测试这项新技术是否可以应用于全身性感染/炎症和神经变性的模型，这越来越被认为是阿尔茨海默病或血管性痴呆引起的痴呆症的重要危险因素。

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.