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治疗（cART）时代，与HIV-1相关的死亡率和发病率 感染已经减少。然而，与艾滋病有关的各种情况以及严重的 非艾滋病事件（SNAE）继续折磨着艾滋病毒感染者（PLWH）。改善的长期 需要从更容易的管理到更好的抑制到功能性治愈的策略。 功能性固化的障碍包括递送活化剂和其他生物活性分子的能力有限 进入HIV的组织储库，特别是中枢神经系统（CNS）中的可能储库。 细胞外囊泡（EV）是一种新型的药物递送方式， 由所有已知细胞类型释放的颗粒，通过穿梭进行细胞间通讯 这些细胞可以将亲本细胞的组分（如蛋白质和RNA）转移到靶细胞。EV导致疾病 发病机制和积极研究，特别是在癌症中，作为生物标志物，在疾病中的演员 过程和潜在的治疗方法。重要的是，EV已被证明可以跨越生物学 屏障，甚至是血脑屏障，并且可以很容易地输送到大脑。因此，电动汽车提供了 将HIV控制或再活化/治愈成分输送到组织储库的绝佳机会， 具有细胞特异性的潜力。 为此，我们组建了一个多学科团队，拥有两个主要的独特资产。第一个是 一种新的小EV-转录激活因子（sEVTA）工具，已经在体外和体内通过 试验.在这个系统中，逆转录病毒反式激活蛋白被特异性地包装到EV中，EV可以 可以进一步用示踪剂和表面肽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CNS疾病。我们会对非人类灵长类动物进行仔细的剂量控制 和分布研究，然后进行sEVTA的优化静脉内和鼻内递送。影响 将在循环和外周组织中使用创新工具评估sEVTA对病毒反弹的影响 储库（目标1），其次是CNS中的储库（目标2）。在目标3中，我们将研究 这些方法的潜在毒性，特别关注中枢神经系统，以及 探索更多针对细胞的方法。 这些研究的目的是使用sEVTA重新激活CNS和CNS中的潜伏逆转录病毒。 外围。然而，该项目还将提供急需的有关电动汽车交付的信息， 在灵长类动物中的分布和功效，可用于开发各种疗法 艾滋病病毒感染和疾病。