Multimodal imaging of antibody-mediated therapy during acute viral encephalitides

描述（由申请人提供）：由于在向中枢神经系统（CNS）递送有效生物药物方面施加的限制以及在不断变化的疾病状态期间难以确定相关治疗剂量，因此治疗嗜神经性病毒存在重大挑战。在感染的一个阶段有用的化合物在以后可能是无用的或甚至是有害的。使问题进一步复杂化的是，可能减轻CNS感染的一些直接后果的药物或抗体可能由于它们的作用模式或它们对血脑屏障通透性的影响而间接地加重疾病。因此，了解潜在治疗剂的分布与CNS中的疾病进展是至关重要的。这只能通过适当的动物模型来实现。我们的目标是使用体内多模式成像方法在这两条链之间建立桥梁：（i）确定两种高度神经致病性生物防御相关因子（尼帕病毒（NiV）和日本脑炎病毒（JEV））的疾病进展;（ii）评估高度中和重组人单克隆抗体（rhMAb）的CNS生物分布和疗效。三个基本要素支撑这项工作计划：获得现有的rhMAb和专业知识，在新的治疗rhMAb的产生;建立急性中枢神经系统感染的小动物模型和显微镜和宏观图像病毒在大脑中的能力;和临床培训，以情境化实验观察的基础上治疗患者的神经系统疾病的多样性。在本项目的探索和发展阶段，提出了四个协同目标：1。修改现有的和确定新的rhMAb的体内抗体成像在中枢神经系统：我们将微观和宏观评估的时间中枢神经系统的生物分布的静脉内交付现有的rhMAb已共轭荧光染料或MRI造影剂钆。同时，将使用相同的多模式成像平台生成、纯化、衍生化、递送和可视化JEV特异性rhMAb。2.确定是否有可能增强rhMAb向大脑的递送：我们将使用两种互补的方法来探索是否有可能增强rhMAb向CNS的摄取。将使用超声随后静脉输注或非典型鼻内途径短暂物理破坏血脑屏障来施用缀合的rhMAb。将按照目标1对生物分布进行时间评估。3.确定在感染期间是否可以检测到CNS递送的rhMAb并评估治疗益处：在开发阶段定义了非疾病状态下的生物分布后，我们将使用多模式成像来评估rhMAb分布以及治疗方法对感染后临床结果的影响。4.确定治疗窗的长度和暴露后治疗所需的最小剂量：我们将评估是否有可能在整个疾病过程中使用rhMAb进行治疗，我们将确定实现最大临床获益所需的最小治疗剂量。 公共卫生相关性：日本脑炎病毒和尼帕病毒在人类中引起非常严重的脑感染，并且大多数在这些感染中存活的人在中枢神经系统中遭受长期问题。目前，没有有效的治疗方法来克服这些短期和长期的问题。通过设计新的治疗药物并增强它们进入大脑的能力，我们希望减少这些病毒的复制。这反过来可以预防甚至消除大脑中的严重疾病，减少感染后死亡的人数，并限制在中枢神经系统中观察到的长期并发症。

DESCRIPTION (provided by applicant): Treating neurotropic viruses presents significant challenges due to the constraints imposed in delivering efficacious biopharmaceuticals to the central nervous system (CNS) and the difficulties determining relevant therapeutic doses during constantly changing disease states. Compounds which are useful at one stage of the infection may be useless or even detrimental later on. Complicating matters further, drugs or antibodies which may mitigate some of the direct consequences of CNS infection may indirectly exacerbate disease due to their mode of action or their effects on blood brain barrier permeability. Therefore it is vital to understand both the distribution of potential therapeutics i concert with disease progression in the CNS. This can only be achieved using appropriate animal models. Our goal is to build a bridge between these two strands using in vivo multimodal imaging approaches (i) to define the disease progression for two highly neuropathogenic biodefense-relevant agents, Nipah virus (NiV) and Japanese encephalitis virus (JEV); and (ii) to assess the CNS biodistribution and efficacy of highly neutralizing recombinant human monoclonal antibodies (rhMAbs). Three essential elements underpin this program of work: access to existing rhMAbs and expertise in the generation of novel therapeutic rhMAbs; the ability to establish small animal models of acute CNS infections and microscopically and macroscopically image viruses in the brain; and the clinical training to contextualize experimental observations based on treating patients with a diversity of neurological conditions. Four synergistic aims are proposed in the exploratory and the developmental phases of this project: 1. Modify existing and identify new rhMAbs for in vivo antibody imaging in the CNS: We will micro- and macroscopically assess the temporal CNS biodistribution of an intravenously delivered existing rhMAb that has been conjugated to fluorescent dyes or the MRI-contrast agent gadolinium. Concurrently, JEV-specific rhMAbs will be generated, purified, derivatized, delivered and visualized using the same multimodal imaging platforms. 2. Determine if it is possible to enhance delivery of rhMAbs to the brain: We will use two complementary approaches to explore if it is possible to enhance the uptake of rhMAbs into the CNS. Either transient, physical disruption of the blood brain barrier using ultrasound followed by intravenous infusion or the atypical intranasal route will be used to administer conjugated rhMAbs. Biodistribution will be assessed temporally as in Aim 1. 3. Determine if CNS-delivered rhMAbs can be detected during infection and assess the therapeutic benefits: Having defined biodistribution in non-diseased states during the development phase we will use multimodal imaging to assess rhMAb distribution and the impact the therapeutics have on clinical outcome after infection. 4. Determine the length of the therapeutic window and the minimal dose needed for post-exposure treatment: We will assess if it is possible to use rhMAbs therapeutically throughout the disease process and we will determine the minimal therapeutic dose required to achieve the maximum clinical benefit. PUBLIC HEALTH RELEVANCE: Japanese encephalitis virus and Nipah virus cause very severe brain infections in humans and most people who survive these infections suffer long term problems in the central nervous system. Currently, there are no effective treatments to overcome these short and long-term problems. By designing new therapeutic agents and enhancing their entry into the brain we hope to reduce the replication of these viruses. This may in turn prevent, or even eliminate the severe disease in the brain, reduce the number of people who die following infection and limit the long term complications observed in the central nervous system.