A Novel CNS-Penetrable Antiretroviral

一种新型中枢神经系统渗透性抗逆转录病毒药物

• 批准号: 8012485
• 负责人: Heidi A Kay
• 金额: $ 25万
• 依托单位: JERICHO SCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-24 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012485
• 关键词: AIDS neuropathy; AIDS/HIV problem; Affect; Anti-Retroviral Agents; Antigen Presentation; Antiviral Agents; Apoptotic; Astrocytes; Autoimmune Process; Autoimmunity; Bacterial Proteins; Blood - brain barrier anatomy; Cells; Cessation of life; Clinical Trials; Disease; Dose; Drug abuse; Evaluation; Exhibits; Failure; Feline Immunodeficiency Virus; Goals; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Human; In Vitro; Incidence; Individual; Infection; Infiltration; Inflammatory Response; Investigational Drugs; Investigational New Drug Application; Knowledge; Lead; Lipopolysaccharides; Microglia; Neuraxis; Neurologic; Neurons; Neurotoxins; Outcome; Pathology; Peripheral Blood Mononuclear Cell; Peripheral Nervous System Diseases; Prevalence; Research Proposals; Source; Suicide; T-Lymphocyte; Therapeutic; Time; Tissues; Toxic effect; Toxin; Treatment Efficacy; United States Food and Drug Administration; Viral; Viral Load result; Viral Proteins; Virus; Virus Diseases; Whole Blood; Work; antiretroviral therapy; base; commercialization; cytokine; in vitro activity; in vivo; macrophage; monocyte; nervous system disorder; neuropathology; neuropsychological; novel; novel therapeutics; pre-clinical; preclinical safety; preclinical study; public health relevance; response; small molecule; uptake

DESCRIPTION (provided by applicant): Since the introduction of highly active antiretroviral therapy (HAART) in the mid-1990's for treatment of human immunodeficiency virus type 1 (HIV-1) infection, overall incidence rates of associated neurological maladies have declined. Unfortunately, the HIV-associated prevalence of both central nervous system (CNS) and peripheral nervous system (PNS) disorders is on the rise, suggesting a failure of antiretroviral therapies to protect neurological tissues despite reducing viral replication. Novel antiretroviral therapeutic approaches are urgently needed for individuals suffering from NeuroAIDS. Most antiretrovirals cannot penetrate into the CNS where both direct and indirect viral burden lead to neuronal damage. Although neurons do not directly support HIV infection, soluble factors and neurotoxins produced by CNS-resident infected cells - such as microglia and astrocytes - are known to lead to neuronal death. Additionally, viral and bacterial proteins can lead to neuronal death through inflammatory responses of CNS- resident cells, even in the absence of direct viral infection. This proposal aims to develop a novel therapeutic suitable for such CNS complications of HIV infection. FX101 is a novel potential antiretroviral therapeutic especially suited for NeuroAIDS, as evidenced by evaluation of virological, immunological and soluble factors in vitro and in vivo, together with its capacity to penetrate the CNS compartment. Specific aims of this project are: 1) demonstrate preclinical safety outcomes and central nervous system uptake of FX101 in vivo; 2) examine in vitro responses of microglial and macrophage cells to FX101 both directly and in concert with viral protein or lipopolysaccharide activation; and 3) evaluate translational therapeutic efficacy of FX101 using human HIV-infected ex vivo whole blood cultures The proposed work will develop along two years and will be continuously evaluated toward the goal of filing an IND application and commercialization of the therapeutic. PUBLIC HEALTH RELEVANCE: This research proposal examines preclinical toxicological studies and human translational efficacy of a novel blood-brain-barrier penetrable therapeutic for the treatment of HIV/AIDS, with or without drug abuse. It is expected that this work will reduce the burden of neurological diseases impacting the central nervous system as a consequence of lentiviral infections and associated pathologies, leading to better treatments for HIV/AIDS-Associated Neuropsychological Disorders.

描述（由申请人提供）：自20世纪90年代中期引入高效抗逆转录病毒疗法（HAART）治疗人类免疫缺陷病毒1型（HIV-1）感染以来，相关神经系统疾病的总体发病率有所下降。不幸的是，HIV相关的中枢神经系统（CNS）和外周神经系统（PNS）疾病的患病率正在上升，这表明抗逆转录病毒疗法未能保护神经组织，尽管减少了病毒复制。新的抗逆转录病毒治疗方法是迫切需要的个人患有神经艾滋病。大多数抗逆转录病毒药物不能渗透到CNS中，直接和间接的病毒负荷都导致神经元损伤。虽然神经元不直接支持HIV感染，但已知CNS驻留感染细胞（如小胶质细胞和星形胶质细胞）产生的可溶性因子和神经毒素会导致神经元死亡。此外，即使在没有直接病毒感染的情况下，病毒和细菌蛋白也可通过CNS驻留细胞的炎症反应导致神经元死亡。该提案旨在开发一种适用于HIV感染的此类CNS并发症的新型治疗药物。FX 101是一种新的潜在的抗逆转录病毒治疗药物，特别适用于NeuroAIDS，通过体外和体内病毒学，免疫学和可溶性因子的评价以及其穿透CNS隔室的能力证明了这一点。该项目的具体目的是：1）证明FX 101的临床前安全性结局和中枢神经系统体内摄取; 2）检查小胶质细胞和巨噬细胞对FX 101的体外反应，包括直接反应和与病毒蛋白或脂多糖活化的反应;和3）使用人HIV-1评估FX 101的翻译治疗功效。感染的离体全血培养物所提出的工作将进行沿着两年，并将朝着提交IND申请和治疗剂商业化的目标进行持续评估。 公共卫生关系：本研究计划检查了一种新型血脑屏障渗透治疗HIV/AIDS的临床前毒理学研究和人类转化功效，无论是否滥用药物。预计这项工作将减少因慢病毒感染和相关病理而影响中枢神经系统的神经系统疾病的负担，从而更好地治疗艾滋病毒/艾滋病相关的神经心理障碍。