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: 9752095
• 负责人: Bharat Ramratnam
• 金额: $ 83.06万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752095
• 关键词: Acquired Immunodeficiency Syndrome; Animal Model; Astrocytes; Biodistribution; Biological; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Blood Cells; Brain; CD4 Positive T Lymphocytes; Cells; 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; Malignant Neoplasms; Measurement; Measures; Membrane; Microdissection; Microglia; Modeling; Monitor; Morbidity - disease rate; Neuraxis; Neurons; Parents; Pathogenesis; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Plasma; Primates; Process; Production; Proteins; RNA; RNA Splicing; Reporter; Retroviridae; SIV; Sampling; Small RNA; Specificity; Spleen; Surface; System; Testing; Therapeutic; TimeLine; 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; macrophage; male; monocyte; mortality; multidisciplinary; neurocognitive disorder; next generation; nonhuman primate; novel; particle; tool; 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.

抽象的 在联合抗逆转录病毒疗法（CART）的时代，与HIV-1相关的死亡率和发病率 感染已减少。然而，各种与艾滋病有关的条件以及严重的条件 非辅助事件（SNAE）继续困扰着感染艾滋病毒（PLWH）的人。长期改善 需要策略，从更轻松的管理到更好的抑制到功能治疗。 功能疗法的障碍包括传递激活剂和其他生物活性分子的能力有限 进入HIV的组织储藏，尤其是中枢神经系统（CNS）中可能的水库。 代表一种新型的传递方式，细胞外囊泡（EV）是双膜结合的 通过所有已知细胞类型释放的颗粒，通过穿梭来进行细胞间通信 对靶细胞的母细胞的成分（例如蛋白质和RNA）。电动汽车有助于疾病 发病机理并正在积极研究，尤其是在癌症中，作为生物标志物，疾病中的参与者 过程和潜在的治疗学。重要的是，已经证明EV可以越过生物学 障碍，甚至是血脑屏障，并且可以轻松地输送到大脑。因此，电动汽车提供了 将艾滋病毒控制或重新激活/治疗的组成部分传递给组织储层的特殊机会， 具有细胞特异性的潜力。 为此，我们组建了一个拥有两个主要的，独特的资产的多学科团队。第一个是 新型的小型EV转录激活剂（SEVTA）工具已经在体外和体内通过 测试。在此系统中，逆转录病毒式激活蛋白被专门包装到EV中，可以 用示踪剂和表面肽进一步官能化，以进行细胞靶向。第二是我们的井 已建立的SIV/猕猴模型已成功地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。我们将进行仔细的非人类灵长类动物剂量 和分布研究，然后优化了塞夫塔斯的静脉内和鼻内递送。效果 病毒反弹上的Sevtas的含量将通过循环和周围组织的创新工具进行评估 水库（AIM 1），然后是中枢神经系统的水库（AIM 2）。在AIM 3中，我们将调查 这些方法的潜在毒性，特别关注中枢神经系统，以及 探索更受细胞靶向的方法。 这些研究的目的是使用SEVTA重新激活中枢神经系统中的潜在逆转录病毒 周边。但是，该项目还将提供有关电动汽车交付的急需信息， 分布和在开发各种疗法方面可以利用的灵长类动物的功效 用于HIV感染和疾病。