Next-generation extracellular vesicle biologics to target central nervous system and peripheral reservoirs of HIV

针对中枢神经系统和外周 HIV 储存库的下一代细胞外囊泡生物制剂

• 批准号: 10594056
• 负责人: Bharat Ramratnam
• 金额: $ 77.07万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-05 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594056
• 关键词: Acquired Immunodeficiency Syndrome; Animal Model; Astrocytes; Binding; Biodistribution; Biological; Biological Assay; Biological Markers; Biological Products; Blood - brain barrier anatomy; Blood Cells; Brain; CD4 Positive T Lymphocytes; Cells; Central Nervous System; Central Nervous System Diseases; Cerebrospinal Fluid; Chemistry; DNA; Data; Development; Disease; Dose; Engineering; Event; Female; Funding; Goals; HIV; HIV Infections; HIV therapy; HIV-1; Health; Heart Diseases; In Vitro; Infection; Inflammation; Inflammatory Response; Intravenous; Length; Lipids; Macaca; Macrophage; Malignant Neoplasms; Measurement; Measures; Membrane; Microdissection; Microglia; Modeling; Monitor; Morbidity - disease rate; Neurons; Parents; Pathogenesis; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Plasma; Primates; Process; Production; Proteins; RNA; RNA Splicing; Reporter; Retroviridae; SIV; Sampling; Small RNA; Specificity; Spleen; Surface; System; Testing; Therapeutic; Tissues; Toxic effect; Tracer; Trans-Activators; Transcription Coactivator; Viral; Viral reservoir; antiretroviral therapy; cell type; cytokine; experience; experimental study; extracellular vesicles; improved; in vivo evaluation; innovation; intercellular communication; lymph nodes; male; monocyte; mortality; multidisciplinary; neurocognitive disorder; next generation; nonhuman primate; novel; particle; timeline; tool; transmission process; treatment response; viral RNA; viral rebound

Abstract In the era of combined antiretroviral therapy (cART), mortality and morbidity associated with HIV-1 infection has been reduced. Nevertheless, a wide range of AIDS-related conditions as well as serious non-AIDS events (SNAEs) continue to afflict people living with HIV (PLWH). Improved long-term strategies are needed, ranging from easier administration to better suppression to functional cure. Barriers to functional cure include a limited ability to deliver activators and other bioactive molecules into tissue reservoirs of HIV, particularly the possible reservoirs in the central nervous system (CNS). Representing a novel mode of delivery, extracellular vesicles (EVs) are double membrane-bound particles, released by all known cell types, that engage in intercellular communication by shuttling components of the parent cell (such as proteins and RNAs) to target cells. EVs contribute to disease pathogenesis and are actively investigated, especially in cancers, as biomarkers, actors in disease processes, and potential therapeutics. Importantly, EVs have been shown to cross biological barriers, even the blood-brain barrier, and can be easily delivered to the brain. EVs thus provide an exceptional opportunity to deliver components of HIV control or reactivation/cure to tissue reservoirs, with potential for cell-specificity. To this end, we have assembled a multidisciplinary team with two major, unique assets. The first is a novel small EV-transcriptional activator (sEVTA) tool that has already passed in vitro and in vivo tests. In this system, retroviral transactivator proteins are specifically packaged into EVs, which can be further functionalized with tracers and surface peptides for cell targeting. The second is our well established SIV/macaque model, which has been used successfully to study retroviral latency, rebound, and retrovirus-associated CNS disease. We will conduct careful nonhuman primate dosing and distribution studies followed by optimized intravenous and intranasal delivery of sEVTAs. Effects of sEVTAs on viral rebound will be assessed with innovative tools in circulating and peripheral tissue reservoirs (Aim 1), followed by reservoirs in the CNS (Aim 2). In Aim 3, we will investigate the potential toxicity of these approaches, with particular focus on the central nervous system, and explore more cell-targeted approaches. The goal of these studies is to use sEVTAs to reactivate latent retroviruses in the CNS and the periphery. However, the project will also provide much-needed information about EV delivery, distribution, and efficacy in primates that can be harnessed in development of a variety of therapies for HIV infection and disease.

摘要 在联合抗逆转录病毒疗法(CART)的时代，与艾滋病毒-1相关的死亡率和发病率 感染已经减少了。尽管如此，与艾滋病相关的各种疾病以及严重 非艾滋病事件(SNAE)继续困扰艾滋病毒感染者(PLWH)。改善了长期 需要采取各种策略，从更容易的管理到更好的抑制，再到功能性治疗。 功能性治疗的障碍包括提供激活剂和其他生物活性分子的能力有限 进入艾滋病毒的组织储存库，特别是中枢神经系统(CNS)可能的储存库。 胞外囊泡(EVS)是一种新的递送方式，具有双重膜结合性 由所有已知细胞类型释放的粒子，通过穿梭进行细胞间通信 亲本细胞的成分(如蛋白质和RNA)到靶细胞。电动汽车引发疾病 发病机制，并被积极研究，特别是在癌症中，作为生物标记物和疾病的参与者 过程和潜在的治疗方法。重要的是，电动汽车已经被证明可以跨越生物 屏障，甚至血脑屏障，可以很容易地传递到大脑。电动汽车因此提供了一种 将HIV控制或重新激活/治愈的组件提供给组织储存器的绝佳机会， 具有潜在的细胞特异性。 为此，我们组建了一个多学科团队，拥有两项重要的、独特的资产。第一个是一个 已在体内外通过的新型小病毒转录激活因子(SEVTA)工具 测试。在这个系统中，逆转录病毒反式激活蛋白被专门包装到EVS中，EVS可以 使用示踪剂和表面肽进一步功能化，以用于细胞靶向。第二个是我们的井 建立了SIV/猕猴模型，该模型已成功用于研究逆转录病毒潜伏期， 反弹，和逆转录病毒相关的中枢神经系统疾病。我们将进行谨慎的非人类灵长类给药 和分布研究，随后优化静脉和鼻腔给药的sEVTA。效应 将使用循环和外周组织中的创新工具来评估病毒反弹的sEVTA 水库(目标1)，其次是中南部的水库(目标2)。在目标3中，我们将调查 这些方法的潜在毒性，特别侧重于中枢神经系统，以及 探索更多针对细胞的方法。 这些研究的目标是使用sEVTA重新激活中枢神经系统中的潜伏逆转录病毒 外围设备。然而，该项目也将提供急需的关于电动汽车交付的信息， 在灵长类动物中的分布和有效性，可用于开发各种治疗方法 用于艾滋病毒感染和疾病。