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.

项目摘要 为了使艾滋病毒治疗方法得到广泛实施，它们需要安全，负担得起， 非常有效。允许将治疗剂输注到 艾滋病毒感染者（PLWH），而不是被制造离体可能代表一个 是实现这一目标的重要一步。在这份申请中，调查人员将他们的专业知识 在mRNA脂质纳米颗粒（mRNA-LNPs）和HIV CAR技术，建议开发 可注射的药剂将靶向并去除潜在的储库。这样做的一个关键优势是， 方法是我们可以靶向组织和细胞，如生殖道或T滤泡 其中CTL被排除或具有减弱的活性的细胞。在目标1中，我们将优化 图4是进行体外研究的这些mRNA-LNP的组成的示意图。一旦铅化合物 鉴定后，我们将在人源化小鼠中测试这些化合物的体内活性。最后，使用 在非人灵长类动物模型中，我们将测试mRNA-LNP复合物降低细胞凋亡的能力。 病毒储存库。