Technologies for the Treatment of Brain Diseases

大挑战是脑部疾病的治疗。脑部疾病包括疼痛、睡眠障碍、精神分裂症、情绪障碍和神经退行性疾病。在任何时候，全世界都有4.5亿人患有精神、神经或行为疾病，2400万人患有痴呆症。脑疾病的治疗受到血脑屏障（BBB）的阻碍，血脑屏障是血液和大脑之间的屏障，由于细胞间毛细血管连接的紧密性、毛细血管细胞的低摄取活性和外排转运体的活性，大多数药物分子不允许通过。先前将药物靶向到大脑并穿过血脑屏障的尝试涉及使用靶向配体，例如用于载体介导摄取或抑制上述外排转运蛋白的小鼠单克隆抗体。然而，在过去二十年中研究的所有基于颗粒的策略（包括使用小鼠单克隆抗体）尚未产生任何临床产品，并且抑制高容量外排转运蛋白（顺便说一下，它不仅局限于血脑屏障）并不是一种可行的临床选择。我们来自学术界和工业界的多学科联盟（GSK）提出了一种基于纳米科学的新策略，该策略基于两个最近的重大发现：a)壳聚糖两亲性纳米颗粒通过静脉注射和重要的口服途径显著提高疏水和多肽药物的中枢活性；b)载脂蛋白E靶向纳米颗粒绕过脑毛细血管外排转运体并穿过血脑屏障，增加药物向大脑的输送。该项目旨在利用这些数据为低脑通透性的多肽和低分子量药物创建一个优化的纳米技术脑传递平台。这些药物类别代表了大部分被困在药物开发瓶颈中的化合物，原因是：a)它们在大脑中的暴露程度较低；b)缺乏合适的大脑靶向策略。候选药物可能用于治疗精神分裂症、疼痛和睡眠障碍。这些化合物及其潜在的适应症与呼吁（针对精神疾病）特别相关，该项目的一个具体产出是治疗精神或神经疾病的候选药物。该项目将涉及颗粒工程的重要水平，其中颗粒基质化学，表面化学（包括发现和评估其他血脑屏障靶向肽）和颗粒大小将系统地变化，并使用体外和动物模型测试这些变化的影响。由此产生的药代动力学、药效学和机制数据将为平台的优化提供信息，这是该项目的最终目标。从根本上说，药物货物的脑渗透机制将在优化纳米系统的过程中进行研究和阐明，这也将满足监管机构和卫生提供者的要求，他们希望为新的卫生技术提供潜在的机制基础。该项目的第二阶段（GSK全力支持）将重点开发基于纳米技术平台的临床药物。公众参与活动将通过我们的nanomedicines.org网站以及科学事件的公众传播进行。该项目的主要受益者将是患者、护理人员和制药行业，因为该平台将为开发新的治疗靶点铺平道路。科学家们的参与，在纳米科学创新、治疗靶点发现、先导物鉴定、药物靶向、将科学概念转化为临床产品和基础脑生理学方面有着悠久的合作历史和良好的记录，使该联盟非常适合实现基于纳米科学的大挑战药物靶向目标。

The Grand Challenge is the treatment of brain diseases. Brain diseases span pain, sleep disorders, schizophrenia, mood disorders and neurodegenerative conditions. At any time 450 million persons worldwide are living with mental, neurological or behavioural illnesses and 24 million people worldwide suffer from dementias. The treatment of brain diseases is hampered by the blood brain barrier (BBB), a barrier between the blood and the brain which does not permit the passage of most drug molecules, due to the tightness of the intercellular capillary junctions, low uptake activity of capillary cells and the activity of efflux transporters. Previous attempts to target drugs to the brain and cross the BBB have involved the use of targeting ligands, e.g. mouse monoclonal antibodies for carrier mediated uptake or the inhibition of the above mentioned efflux transporters. However all of the particulate-based strategies (including the use of mouse monoclonal antibodies) that have been investigated over the last two decades have yet to yield any clinical products and the inhibition of the high capacity efflux transporters, which incidentally are not merely confined to the BBB, is not a viable clinical option. Our multidisciplinary consortium drawn from academia and industry (GSK) propose a new nanoscience based strategy founded on two recent significant findings: a) chitosan amphiphile based nanoparticles significantly increase the central activity of hydrophobic and peptides drugs via the intravenous and crucially oral routes, b) apolipoprotein E targeted nanoparticles bypass the brain capillary efflux transporters and cross the BBB, increasing drug delivery to the brain. The project aims to use these data to create an optimised nanotechnology brain delivery platform for peptides and low molecular weight drugs with low brain permeability. These drug classes represent the bulk of the compounds which are trapped in the drug development bottleneck due to: a) their poor brain exposure and b) the absence of suitable brain targeting strategies. Candidate drugs to be used are potential treatments for schizophrenia, pain and sleep disorders. These compounds and their potential indications are particularly relevant to the call (targeting psychiatric diseases) and a specific output of the project is a candidate medicine for the treatment of psychiatric or neurological disorders. The project will involve a significant level of particle engineering, where particle matrix chemistry, surface chemistry (including the discovery and evaluation of other BBB targeting peptides) and particle size will be systematically varied and the impact of these variations tested using in vitro and animal models. The resulting pharmacokinetic, pharmacodynamic and mechanistic data will inform the optimisation of the platform which is the ultimate goal of the project. Fundamentally the mechanism of brain permeation of the drug cargoes will be studied and elucidated en route to the optimised nanosystem and this will also fulfil a requirement of regulators and health providers, who desire an underlying mechanistic basis for new health technologies. Stage 2 of the project (GSK fully supported) will focus on the development of a clinical medicine based on the nanotechnology platform.Public engagement activities will occur via our nanomedicines.org website and also via public communication of science events. The key beneficiaries of the project will be patients, carers and the pharmaceutical industry as the platform will pave the way for novel therapeutic targets to be exploited. The engagement of scientists, with a past history of collaboration and a strong track record in nanoscience innovation, therapeutic target discovery, lead identification, drug targeting, translating scientific concepts to clinical products and basic brain physiology makes the consortium ideally suited to deliver the nanoscience based drug targeting goals of the Grand Challenge.