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。

• 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
• 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

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。艾滋病治疗的进展是无可争议的，有效的 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 接受治疗。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。 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 跨越血脑屏障的 ART。此外，由于大脑中的活跃感染，高达 50% 的患者 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艾滋病毒复制并 治疗或预防艾滋病毒感染者 (PLWH) 的手部感染。寻找更有效的新治疗剂 并且不良影响正在减少。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一类疗法。尽管如此，由于这些生物制剂体积较大， 全身给药后到达大脑的可能性甚至低于 cART。因此，有利于 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： 在大脑中持续释放高效的 bNAb。据此，我们假设 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) 小鼠艾滋病毒建模； (ii) 发展艾滋病毒 bNAB； (iii) 基于干细胞的疗法和干细胞基因工程； (iv) 图像引导动脉内注射 注射将整体细胞输送到大脑。在我们的前期工作中，我们已经表明，动脉内 递送的 GRP 可以穿过血脑屏障，有可能成为本地产生 HIV 的载体 脑实质中的 bNAb。在我们提出的研究中使用 GRP 的主要优点是它们的鲁棒性 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 甚至移植后数年。因此，它将满足 bNAB 引起的长期作用的需要 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 血脑屏障控制和根除中枢神经系统中的艾滋病毒储存库。如果我们的项目证明安全 和功效，它可以迅速转化为临床环境，深刻影响许多感染者。