Immunophilin ligands for HIV dementia and neuropathy

HIV 痴呆和神经病的亲免素配体

• 批准号: 6677803
• 负责人: AVINDRA NATH
• 金额: $ 141.41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-08 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6677803
• 关键词: AIDS /HIV neuropathy; AIDS dementia complex; HIV infections; clinical research; dementia; human subject; ligands; peptidylprolyl isomerase

As patients are living longer with HIV infection, neurological complications such as dementia and peripheral neuropathy are becoming more prevalent and an important cause of morbidity in this population. To date, however, there is no effective treatment for these complications. Both the brain and the dorsal root ganglia show evidence of neurodegeneration while the virus replicates in glial cells or infiltrating monocytes. This suggests an important role for neuroprotective and neurotrophic modes of treatment for these conditions. This program project grant brings together researchers from several disciplines to closely interact with one another to develop new modes of treatment. During the duration of this program project we propose to conduct basic mechanistic in vitro studies using unique in vitro models for HIV dementia and peripheral neuropathy and to conduct animal studies as well as a phase 2 clinical trial. These projects will closely interact with a pharmaceutical company that has developed some novel immunophilin ligands that are highly potent neuroprotective and neurotrophic agents. We have taken a bench to bedside approach to evaluate their clinical use. A unique strength of this proposal is that it will identify compounds that are useful for treating both HIV dementia and peripheral neuropathy, since these conditions may coexist and occasionally may be difficult to differentiate. We have proposed five interactive projects and one core. Project l will determine the use of these agents in a human in vitro model for HIV dementia, Project 2 will similarly study the agents in the context of dorsal root ganglia neurons, Project 3 will determine subcellular mechanisms involved in neuroprotection. Project 4 will determine the use of a select compound in an SIV model of HIV dementia and peripheral neuropathy. Project 5 will conduct a phase 2 clinical trial of the compound identified as the lead candidate from the above projects. During the initial years of the Program project animal and clinical projects will develop and validate some novel tests that would serve as critical outcome measures during the trial. An administrative core will coordinate the interactions between all the projects and each of the researchers.

随着艾滋病毒感染者的寿命延长，痴呆症等神经系统并发症也随之而来。 周围神经病变变得越来越普遍，并且是该人群发病的重要原因。然而，迄今为止，还没有针对这些并发症的有效治疗方法。当病毒在神经胶质细胞或浸润单核细胞中复制时，大脑和背根神经节都显示出神经变性的证据。这表明神经保护和神经营养模式对这些疾病的治疗具有重要作用。该计划项目资助汇集了来自多个学科的研究人员，彼此密切互动，开发新的治疗模式。在该计划项目期间，我们建议使用独特的 HIV 痴呆和周围神经病变体外模型进行基本的体外机制研究，并进行动物研究以及 2 期临床试验。这些项目将与一家制药公司密切合作，该公司已开发出一些新型亲免素配体，这些配体是高效的神经保护剂和神经营养剂。我们采取了从实验室到临床的方法来评估它们的临床用途。该提案的独特优势在于，它将鉴定出可用于治疗艾滋病毒痴呆和周围神经病变的化合物，因为这些病症可能共存，有时可能难以区分。我们提出了五个互动项目和一个核心项目。项目1将确定这些药物在人类HIV痴呆体外模型中的使用，项目2将类似地在背根神经节神经元的背景下研究这些药物，项目3将确定参与神经保护的亚细胞机制。项目 4 将确定在 HIV 痴呆和周围神经病变的 SIV 模型中使用选定的化合物。项目5将对上述项目中确定的主要候选化合物进行2期临床试验。在该计划的最初几年，动物和临床项目将开发和验证一些新的测试，这些测试将作为试验期间的关键结果衡量标准。管理核心将协调所有项目和每个研究人员之间的互动。