Image-guided intra-arterial administration of antibody-releasing glial progenitors to control the HIV CNS reservoir.

图像引导动脉内注射抗体释放神经胶质祖细胞来控制 HIV 中枢神经系统储库。

基本信息

批准号：
10684314
负责人：
Alonso Heredia
金额：
$ 60.01万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684314
关键词：
Address Adverse effects Animal Model Anti-Retroviral Agents Antibodies Antibody Formation Arteriogram Astrocytes Binding Binding Sites Biological Products Blood Blood - brain barrier anatomy Brain Cardiovascular system Cells Chronic Clinical Cognitive Development Diffusion Dose Drug resistance Engineering Engraftment Face GRP gene Genetic Engineering Goals HIV HIV Envelope Protein gp120 HIV Infections HIV therapy HIV-associated neurocognitive disorder Human Individual Infection Intra-Arterial Infusions Intra-Arterial Injections Ischemia Lymphocyte Macrophage Magnetic Resonance Imaging Medial Metabolic Methodology Methods Microglia Modeling Moods Morbidity - disease rate Motor Mus Neurologic Neuropathogenesis Oligodendroglia Penetration Peripheral Persons Pharmaceutical Preparations Phenotype Plasma Positioning Attribute Positron-Emission Tomography Predisposition Production Property Reproducibility Research Risk Safety Testing Therapeutic Therapeutic Agents Time Toxic effect Translating Transplantation Vial device Viral Viral Load result Viremia Virus Work antiretroviral therapy bioluminescence imaging blood-brain barrier crossing brain cell brain parenchyma cerebrovascular clinical development comorbidity dosage engineered stem cells experience image guided innovation neuroinflammation neutralizing antibody novel novel strategies novel therapeutics prevent progenitor resistant strain stem cell therapy stem cells tool trafficking vector

项目摘要

This proposal responds to RFA DA-22-010. Progress in the treatment of HIV is undisputed with potent combined antiretroviral therapy (cART), allowing most individuals to live relatively healthy for decades while receiving treatment. Although cART can maintain plasma HIV viral suppression to undetectable levels, discontinuation of cART invariably results in a rapid rebound of plasma viremia. cART’s inability to cure HIV is due, at least in part, to persistent HIV reservoirs, such as those in the CNS, and to the limited ability of most ARTs to cross the blood-brain barrier. In addition, because of active infection in the brain, up to 50% of those infected may develop a spectrum of cognitive, motor, and/or mood problems collectively known as HIV- Associated Neurocognitive Disorder (HAND). Our long-term goal is to control HIV replication in CNS and to treat or prevent HAND in people living with HIV (PLWH). Search for new therapeutic agents with more potency and fewer adverse effects is underway. For example, broadly HIV-neutralizing antibodies (bNAbs) are a new class of therapeutics recently recognized to eliminate viremia. Still, due to their large size, these biologics are even less likely than cART to reach the brain after systemic administration. Therefore, the tools that facilitate the effective and long-lasting administration of these potent and safe drugs to the brain are urgently needed as they can solve the challenging problem of the brain’s HIV reservoir. The goal of this proposal is to control HIV replication in the brain by sustained delivery of bNAbs.Therefore, this proposal is based on the premise that the inability of cART to inhibit HIV replication in the CNS can be overcome by a complementary strategy that provides sustained release of highly efficacious bNAbs in the brain. Accordingly, we hypothesize that sustained release of genetically-encoded HIV bNAbs in the brain by ex vivo engineered and transplanted glial progenitor cells (GRPs) can suppress HIV replication and decrease HIV-induced neuropathogenesis. We assembled an interdisciplinary team with expertise in (i) modeling HIV in mice; (ii) developing HIV bNABs; (iii) stem cell-based therapy and genetic engineering of stem cells; (iv) image-guided intraarterial injection for global cell delivery to the brain. In our preliminary work, we have shown that intra-arterially delivered GRPs can cross the blood-brain barrier, potentially serving as carriers for local production of HIV bNAbs in brain parenchyma. The main advantage of using GRPs in our proposed studies is their robust engraftment, differentiation towards oligodendrocytes and astrocytes, and persistence in the brain for months and even years after transplantation. Thus, it will meet the need for long-lasting effects elicited by bNABs to prevent HIV replication in the CNS and may help eradicate the CNS reservoir of HIV. Overall, we propose an innovative cell-based strategy that addresses poor drug penetration across the blood-brain barrier to control and eradicate the HIV reservoir in the CNS. If our project demonstrates safety and efficacy, it could be rapidly translated into the clinical settings, profoundly impacting many PLWH.

该提案对RFA DA-22-010做出了回应。艾滋病毒治疗的进展无可争议结合抗逆转录病毒疗法（CART），使大多数人几十年来生活相对健康接受治疗。尽管购物车可以维持血浆HIV病毒抑制至无法检测到的水平，停药始终导致血浆病毒血症的快速反弹。购物车无法治愈艾滋病毒是至少部分归因于CNS中的持续性艾滋病毒水库，以及大多数人的能力有限的能力跨越血脑屏障的艺术。另外，由于大脑中的活跃感染，其中多达50％受感染的可能形成一系列认知，运动和/或情绪问题，共同被称为HIV- 相关的神经认知障碍（手）。我们的长期目标是控制中枢神经系统的艾滋病毒复制治疗或防止艾滋病毒（PLWH）患者的手。搜索具有更大效力的新治疗剂正在进行的不利影响正在进行中。例如，广泛的HIV中和抗体（BNAB）是一种新的最近被认为可以消除病毒血症的治疗剂类别。尽管如此，由于它们的尺寸较大，这些生物制剂是全身给药后，甚至比购物车到达大脑的可能性更低。因此，促进的工具迫切需要对这些潜力和安全药物对这些潜在和安全的药物的有效和持久给药，因为他们可以解决大脑艾滋病毒水库的挑战问题。该提议的目的是控制艾滋病毒因此，通过持续交付BNAB在大脑中的复制。因此，该提案是基于这样的前提。可以通过一个完整的策略来克服CAR抑制中枢神经系统中HIV复制的无法抑制艾滋病毒复制的能力提供大脑中高效的BNAB的持续释放。据此，我们假设通过体内和移植神经胶质在大脑中持续释放遗传编码的HIV BNAB 祖细胞（GRP）可以抑制HIV复制并减少HIV诱导的神经病发生。我们组建了一个跨学科团队，在（i）在小鼠中建模艾滋病毒方面具有专业知识；（ii）发展艾滋病毒 bnabs; （iii）干细胞基于干细胞的治疗和基因工程；（iv）图像引导的内部注射全球细胞向大脑输送。在我们的初步工作中，我们已经表明了动脉内递送的GRP可以越过血脑屏障，有可能用作局部生产HIV的携带者脑实质中的bnabs。在我们提出的研究中使用GRP的主要优点是它们的强大植入，分化向少突胶质细胞和星形胶质细胞，以及大脑的持久性数月甚至在移植后数年。那就是，它将满足BNAB引起的长期效果的需求防止中枢神经系统中的艾滋病毒复制，并可能有助于艾滋病毒的中枢神经系统储藏。总体而言，我们提出了一种创新的基于细胞的策略，该策略解决了整个药物的渗透率不佳 CNS中的HIV储存剂控制和放射性的血脑屏障。如果我们的项目证明了安全轻松，它可以迅速转化为临床环境，从而深刻影响许多PLWH。