Targeting CNS HIV reservoirs across the blood-brain barrier

跨越血脑屏障靶向中枢神经系统艾滋病毒储存库

• 批准号: 8544744
• 负责人: MATTHEW LEVY
• 金额: $ 25.42万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-25 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544744
• 关键词: Acids; Animal Model; Anti-HIV Agents; Antibodies; Biological Assay; Blood - brain barrier anatomy; Blood Circulation; Blood capillaries; Brain; Brain Diseases; Cells; Chemistry; Clinic; Collaborations; Drug Combinations; Drug Delivery Systems; Endothelial Cells; Evolution; Exhibits; Future; HIV; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV therapy; HIV-1; Health; Highly Active Antiretroviral Therapy; Human; In Vitro; Infection; Inflammatory; Laboratories; Length; Ligands; Mediating; Modality; Modeling; Morbidity - disease rate; Neurons; Neurotoxins; Pathogenesis; Patients; Penetration; Pharmaceutical Preparations; Prevalence; Property; Proteins; RNA; Recombinants; Research; Resistance; Role; Route; System; Testing; Therapeutic; Therapeutic antibodies; Transferrin; Transferrin Receptor; Variant; Viral Proteins; Virion; aptamer; base; capillary; chemokine; combat; cytokine; design; improved; in vitro Model; in vivo; killings; macrophage; monolayer; nervous system disorder; neurotoxic; neurotoxicity; neutralizing antibody; next generation; novel; nuclease; prevent; public health relevance; research study; tat Protein; therapeutic target

DESCRIPTION (provided by applicant): The prevalence of HIV-associated neurological disorders (HAND) is on the rise despite Highly Active Anti-Retroviral Therapy (HAART). The pathogenesis of HAND is primarily due to neurotoxic viral proteins such as HIV-1 gp120 and Tat due to the replication of HIV in the brain. Antiretrovirals have variable efficiencies in crossing he blood brain barrier and thus being unable to eliminate HIV-1 in the CNS or in reducing the neurotoxic viral proteins. To overcome this problem, we propose to employ a modular, aptamer-based approach to deliver therapeutics designed to neutralize HIV-1 and inhibit neurotoxic viral proteins hiding behind the blood brain barrier (BBB). We will develop the next generation of delivery agents that can transcytose the BBB, specifically target HIV and consequently achieve higher effective drug concentrations in the CNS to be able to combat and neutralize HIV-1 and its toxic byproducts. There will be two specific aims. In Aim 1, we will target HIV reservoirs in te CNS using previously selected anti-transferrin receptor (hTfR) aptamers that can cross an in vitro model BBB composed of Human Brain Microvascular Endothelial Cells (HBMECs). Using these aptamers and our in vitro BBB model, we will develop a strategy to deliver therapeutic antibodies, aptamers or other molecules across the BBB and attempt to neutralize recombinant gp120 or Tat protein-mediated neuronal killing or to prevent HIV-infection of macrophages. In Aim 2, using a novel cell-based SELEX approach (selective evolution of ligands by exponential amplification) and using a flow-based dynamic in vitro blood brain barrier (DIV-BBB; Flowcel Inc.) which accurately reproduces the BBB in vivo, we seek to identify RNA aptamers that can specifically cross the BBB and will subsequently adapt these for drug delivery across the BBB.

描述（由申请人提供）：尽管有高效抗逆转录病毒疗法（HAART），但 HIV 相关神经系统疾病（HAND）的患病率仍在上升。 HAND的发病机制主要是由于HIV-1 gp120和Tat等神经毒性病毒蛋白在大脑中复制所致。抗逆转录病毒药物穿过血脑屏障的效率各不相同，因此无法消除中枢神经系统中的 HIV-1 或减少神经毒性病毒蛋白。为了克服这个问题，我们建议采用模块化、基于适体的方法来提供旨在中和 HIV-1 并抑制隐藏在血脑屏障 (BBB) 后面的神经毒性病毒蛋白的治疗方法。我们将开发下一代传递剂，可以转胞吞 BBB，专门针对 HIV，从而在中枢神经系统中实现更高的有效药物浓度，从而能够对抗和中和 HIV-1 及其有毒副产物。将有两个具体目标。在目标 1 中，我们将使用先前选择的抗转铁蛋白受体 (hTfR) 适体来靶向 CNS 中的 HIV 储存库，该适体可以穿过由人脑微血管内皮细胞 (HBMEC) 组成的体外模型 BBB。利用这些适体和我们的体外 BBB 模型，我们将开发一种策略，跨 BBB 传递治疗性抗体、适体或其他分子，并尝试中和重组 gp120 或 Tat 蛋白介导的神经元杀伤或预防巨噬细胞的 HIV 感染。在目标 2 中，我们使用一种新型的基于细胞的 SELEX 方法（通过指数扩增选择性进化配体）并使用基于流动的动态体外血脑屏障（DIV-BBB；Flowcel Inc.）在体内精确复制 BBB，我们寻求鉴定可以特异性穿过 BBB 的 RNA 适体，并随后将其用于跨 BBB 的药物递送。