Multimodal imaging of antibody-mediated therapy during acute viral encephalitides

描述（由申请人提供）：由于向中枢神经系统（CNS）提供有效的生物药物所施加的限制以及在不断变化的疾病状态中确定相关治疗剂量的困难，治疗嗜神经病毒面临重大挑战。在感染的某一阶段有用的化合物可能在以后就无用甚至有害了。使问题进一步复杂化的是，药物或抗体可能减轻中枢神经系统感染的一些直接后果，但由于它们的作用方式或它们对血脑屏障通透性的影响，可能间接加剧疾病。因此，了解潜在治疗药物的分布与中枢神经系统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。我们的目标是利用体内多模态成像方法在这两条链之间建立一座桥梁(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）评估高度中和的重组人单克隆抗体（rhmab）的中枢神经系统生物分布和疗效。支持这一工作计划的三个基本要素：获得现有的rhmab和产生新型治疗性rhmab的专业知识；建立急性中枢神经系统感染的小动物模型以及大脑中显微镜和宏观图像病毒的能力；以及临床训练，将实验观察与治疗各种神经系统疾病的患者结合起来。在该项目的探索和发展阶段提出了四个协同目标：1。修改现有的和鉴定新的rhMAb用于中枢神经系统的体内抗体成像：我们将从微观和宏观上评估静脉注射的现有rhMAb与荧光染料或mri造影剂钆偶联的时间中枢神经系统生物分布。同时，将使用相同的多模态成像平台生成、纯化、衍生、递送和可视化jev特异性rhmab。2. 确定是否有可能增强rhmab向大脑的传递：我们将使用两种互补的方法来探索是否有可能增强rhmab进入中枢神经系统的摄取。要么使用超声对血脑屏障进行短暂的物理破坏，然后静脉输注，要么使用非典型的鼻内途径给药。生物分布将在目标1中进行临时评估。3. 确定在感染期间是否可以检测到cns传递的rhMAb并评估治疗效果：在开发阶段确定了非患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. 确定治疗窗口的长度和暴露后治疗所需的最小剂量：我们将评估是否可能在整个疾病过程中使用rhmab进行治疗，我们将确定获得最大临床益处所需的最小治疗剂量。

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.