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.
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.
