Eliminating the latent reservoir by targeted in vivo delivery of HIV-specific CARs

通过体内靶向递送 HIV 特异性 CAR 消除潜在病毒库

• 批准号: 10593735
• 负责人: Hamideh Parhiz
• 金额: $ 68.92万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-06 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593735
• 关键词: Antibodies; Area; B-Lymphocytes; CD4 Positive T Lymphocytes; COVID-19 vaccine; CXCR4 gene; Cells; Clinic; Complex; Development; Effectiveness; Encapsulated; Environment; Exclusion; FDA approved; Genetic; Gills; Goals; HIV; HIV Infections; Half-Life; Immune; Immune system; Immunotherapy; In Vitro; Individual; Injectable; Lead; Length; Macrophage; Messenger RNA; Modeling; Nucleosides; Persons; Phase I Clinical Trials; Pilot Projects; Proteins; RNA; Research Personnel; Resistance; Site; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Vertebral column; Viral reservoir; Viremia; Virus; antiretroviral therapy; cell type; design; experimental study; humanized mouse; immune clearance; in vivo; lipid nanoparticle; lymph nodes; manufacture; monocyte; nonhuman primate; reproductive; success; targeted delivery; tool; trafficking; vaccine delivery

Project Summary For HIV cure approaches to be widely implemented, they will need to be safe, affordable and highly effective. The development strategies that allow therapeutic agents to be infused into people living with HIV (PLWH) rather than being manufactured ex vivo may represent an important step to reaching this goal. In this application, the investigators merged their expertise in mRNA lipid nanoparticles (mRNA-LNPs) and HIV CAR technology to propose to develop injectable agents that will target and remove the latent reservoir. A key advantage of this approach is that we can target tissues and cells such as the reproductive track or T follicular cells where CTLs are either excluded or have diminished activity. In Aim 1, we will optimize the composition of these mRNA-LNPs performing in vitro studies. Once lead compounds are identified, we will test these in humanized mouse for in vivo activity. Finally, using a state of the art non-human primate model we will test the ability of mRNA-LNP complexes to reduce the viral reservoir.

项目概要 为了广泛实施艾滋病毒治疗方法，它们需要安全、负担得起和 非常有效。允许将治疗剂注入体内的开发策略 艾滋病毒感染者（PLWH）而不是体外制造的人可能代表了一种 实现这一目标的重要一步。在这个应用程序中，研究人员融合了他们的专业知识 mRNA脂质纳米颗粒（mRNA-LNPs）和HIV CAR技术拟开发 注射剂将瞄准并清除潜在的储存库。这样做的一个关键优势 方法是我们可以针对组织和细胞，例如生殖道或滤泡 T CTL 被排除或活性减弱的细胞。在目标 1 中，我们将优化 这些 mRNA-LNP 的组成进行体外研究。一旦铅化合物 确定后，我们将在人源化小鼠中测试它们的体内活性。最后，使用状态 在非人类灵长类动物模型中，我们将测试 mRNA-LNP 复合物减少 病毒库。