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：
10512770
负责人：
Alonso Heredia
金额：
$ 60.43万
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/10512770
关键词：
Address Adverse effects Animal Model Anti-Retroviral Agents Antibodies Antibody Formation Arteriogram Astrocytes Binding Sites Biological Products Blood Blood - brain barrier anatomy Brain Brain imaging Cardiovascular system Cells Chronic Clinical Cognitive Development Diffusion Dose Drug resistance Engineering Engraftment Face Genetic Engineering Goals HIV HIV Envelope Protein gp120 HIV Infections HIV therapy HIV-associated neurocognitive disorder Human Individual Infection Intra-Arterial Injections Lead Lymphocyte 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 Progenitor Cell Engraftment 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 base bioluminescence imaging brain cell brain parenchyma cerebrovascular clinical development comorbidity dosage engineered stem cells experience image guided innovation macrophage 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.

该提案是对 RFA DA-22-010 的回应，在治疗艾滋病毒方面取得了无可争议的有效进展。联合抗逆转录病毒疗法（cART），使大多数人能够相对健康地生活数十年，同时尽管 cART 可以将血浆 HIV 病毒抑制维持在不可检测的水平，停止 cART 总是会导致血浆病毒血症迅速反弹，而 cART 无法治愈 HIV。至少部分是由于持续存在的艾滋病毒储存库，例如中枢神经系统中的储存库，以及大多数人的能力有限此外，由于大脑中的活动性感染，ART 可以穿越血脑屏障。感染者可能会出现一系列认知、运动和/或情绪问题，统称为 HIV- 相关神经认知障碍 (HAND) 我们的长期目标是控制中枢神经系统中的 HIV 复制并治疗或预防 HIV 感染者 (PLWH) 的 HAND 寻找更有效的新治疗药物。例如，广泛的 HIV 中和抗体（bNAb）是一种新的药物。最近被认为可以消除病毒血症的一类疗法尽管如此，由于它们的体积较大，这些生物制剂仍然是一种有效的治疗方法。全身给药后到达大脑的可能性甚至比 cART 更小。迫切需要对大脑有效且持久地施用这些有效且安全的药物，因为他们可以解决大脑艾滋病毒储存库这一具有挑战性的问题。该提案的目标是控制艾滋病毒。通过持续递送 bNAb 在大脑中进行复制。因此，该提议基于以下前提： cART 无法抑制中枢神经系统中的 HIV 复制，可以通过补充策略来克服：提供大脑中高效 bNAb 的持续释放。因此，我们对此进行了混乱。通过离体工程和移植的神经胶质细胞在大脑中持续释放基因编码的 HIV bNAb 祖细胞 (GRP) 可以抑制 HIV 复制并减少 HIV 诱导的神经病变。我们组建了一个跨学科团队，其专业知识包括：(i) 对小鼠进行 HIV 建模；(ii) 开发 HIV； bNAB；(iii) 基于干细胞的治疗和干细胞基因工程；(iv) 图像引导动脉内治疗；在我们的初步工作中，我们已经证明了动脉内注射将整个细胞输送到大脑。递送的 GRP 可以穿过血脑屏障，有可能成为本地产生艾滋病毒的载体在我们提出的研究中使用 GRP 的主要优点是其稳健性。植入、分化为少突胶质细胞和星形胶质细胞，并在大脑中持续数月因此，它可以满足 bNAB 产生持久作用的需要。防止艾滋病毒在中枢神经系统中复制，并可能有助于根除中枢神经系统中的艾滋病毒储存库。总的来说，我们提出了一种基于细胞的创新策略，解决药物在整个系统中渗透不良的问题如果我们的项目证明安全的话，血脑屏障可以控制和根除中枢神经系统中的艾滋病毒储存库。和功效，它可以迅速转化为临床环境，深刻影响许多感染者。