Treatment of acute west nile virus diease and neurological sequelea

该项目的长期目标是发现西尼罗河病毒(WNV)的治疗方法，当 在病毒感染中枢神经系统(CMS)和发展为 神经后遗症，因为目前还没有已知的治疗方法。理由：我们已经确定了两个 抗病毒药物，前3年，具有治疗西尼罗河病毒病的潜力。为了促进临床前工作 在药物的开发过程中，我们使用了电生理测量来识别啮齿动物 感染急性期后持续的神经病理。我们现在准备好在这项提案中回答 关于病毒性脑炎致病机制或逆转机制的重要基本问题 持久的神经病理学，并发现有效的治疗方法，对实现 RMRCE。具体目的：1.提高E16和T-705的疗效。一种治疗性抗体E16将是 突变，以消除与一种受体的相互作用，该受体介导免疫球蛋白从大脑流出，重新进入 血。此外，一种20聚体的狂犬病病毒糖蛋白将被用来通过血脑进入E16 屏障(BBB)进入中枢神经系统。活性吡嗪类似物T-705的药效和核磷酸化作用 直接在神经元中进行验证，然后将其直接注入大脑或鞘内注射 给仓鼠注射，以直接测试其在中枢神经系统的疗效。2.在啮齿动物中鉴定致病机理 从急性病毒性脑炎过渡到持续性神经病理学。临床电生理 测量中枢神经系统三个解剖区域功能的分析将用于 确定具有持续性神经病理的啮齿类动物。免疫组织化学、体温、动物 运动/活动和功能运动测试也将被用来比较急性 感染和持续性神经病理。3.验证抗WNV药物在啮齿动物体内的临床前疗效 模特们。将研究改进的抗病毒药物对急性WNV脑炎和 顽固的神经病理。我们预计，在推迟治疗后，改进的疗法仍将有效 开始治疗，在持续的神经病理期间治疗可能有效。 根据已发表的机制，神经保护剂将在持续性神经病理学中进行评估。 模特。两家公司将合作开发这些疗法的临床应用。这项研究项目适合 在RMRCE综合研究中心内，该中心将专注于病毒治疗，并将直接与RP 3.2互动。

The long-term objective of this project is to discover treatments for West Nile virus (WNV) when administered after the virus has infected the central nervous system (CMS) and after the development of neurological sequelae, since no known therapy is currently available. Rationale: We have identified two antiviral agents, in the prior 3 years, with the potential for treating WNV disease. To facilitate pre-clinical development of the drugs, we have employed electrophysiological measurements to identify rodents with persistent neuropathology after the acute phase of infection. We are now poised in this proposal to answer important basic questions about pathogenic mechanisms causing or reversing viral encephalitis and persistent neuropathology, and to discover effective therapies that are important for the objectives of the RMRCE. Specific Aims: 1. Improve the efficacy of E16 and T-705. A therapeutic antibody, E16, will be mutated to remove the interaction with a receptor that mediates IgG efflux out of the brain back into the blood. Additionally, a 20-mer rabies virus glycoprotein will be used to influx E16 across the blood brain barrier (BBB) into the CNS. The efficacy and ribophosphorylation of an active pyrazine analog, T-705, will be verified directly in neurons, after which it will be administered directly into the brain or by intrathecal administration of hamsters to directly test its efficacy in the CNS. 2. Identify in rodents the pathogenesis for the transition from acute viral encephalitis to persisting neuropathology. Clinicoelectrophysiological assays that measure the function of three anatomical areas of the CNS will be used to identify rodents with persistent neuropathology. Immunohistochemistry, body temperature, animal motion/activity, and functional motor tests will also be employed to make comparisons between the acute infection and persisting neuropathology. 3. Verify the pre-clinical efficacy of anti-WNV drugs in rodent models. Improved antiviral drugs will be investigated for efficacy against acute WNV encephalitis and persisting neuropathology. We expect that improved therapeutics will still be efficacious after delaying the initiation of treatment, and that treatments may be effective during persisting neuropathology. Neuroprotective agents, based on published mechanisms, will be evaluated in the persistent neuropathology model. Two companies will collaborate for clinical development of these therapies. This research project fits within the RMRCE Integrated Research Focus on Viral Therapeutics, and will interact directly with RP 3.2.