Nonhuman Primate Core

非人类灵长类核心

基本信息

批准号：
10468650
负责人：
HANS-PETER KIEM
金额：
$ 90.62万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-07 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10468650
关键词：
Alkylating Agents Animal Model Animals Autologous Biological Assay Busulfan CCR5 gene Case Study Cells Cellular Immunity Clinic Clinical Clinical Trials Consultations Custom Data Eye Fumarates Future Gene Delivery Gene-Modified Genetic Engineering Goals HIV HIV Infections HIV-1 Hematopoietic stem cells Humoral Immunities Immune Individual Infection Infusion procedures Investigation Lentivirus Vector Letters Macaca Macaca nemestrina Measures Methods Modeling Modification Monitor Patients Pharmaceutical Preparations Plasma Play Positioning Attribute Primates Procedures Prodrugs Production Progenitor Cell Engraftment Protocols documentation Publishing Regimen Research Role Sampling Schedule Series Stem cell transplant Supportive care Tenofovir Testing Therapeutic Thioguanine Titrations Toxic effect Translating Transplantation Vaccine Therapy Viral Load result Virus Washington Work animal care antiretroviral therapy base combinatorial conditioning design emtricitabine experience experimental study gene therapy gene transplantation for gene therapy hematopoietic transplantation in vivo in vivo engraftment in vivo evaluation intravenous administration lead candidate neutralizing antibody neutralizing vaccine nonhuman primate pinacolyl methylphosphonic acid pre-clinical scale up simian human immunodeficiency virus small hairpin RNA synergism vector

项目摘要

Core C: Project Summary/Abstract Transplantation of hematopoietic stem and progenitor cells (HSPCs) underlies the only known case of HIV-1 functional cure. Over 12 years after this pioneering clinical case study, however, substantial improvements are needed in order to apply this case study to a broader spectrum of HIV+ individuals. The overarching goal of our U19 consortium is to identify candidate strategies to safely and effectively modify a patient's own HSPCs to resist HIV infection, and simultaneously enhance their ability to recognize and destroy infected cells. The Nonhuman Primate (NHP) Core will play a central role in organizing preclinical aspects of the approaches proposed by each project in our group, maintaining a focus on translationally relevant features that are best suited for future trials in patients. In Project 1 (Kitchen), we will generate a series of 12 NHPs that are transplanted with autologous, gene-modified HSPCs. These cells will express a promising virus-specific immune effector molecule known as CD4CAR, in combination with other promising therapies such as broadly neutralizing antibodies (bNAbs), and therapeutic vaccination. CD4CAR-modified HSPC progeny, in combination with bNAbs and vaccine-specific cells, represent a formidable and synergistic approach to target virus persistence. In Project 2 (Morizono), we will focus on approaches to gene-modify HSPCs without removing them from the body, studying a total of 9 NHP. So-called “in vivo delivery” approaches will significantly enhance the applicability of anti-HIV gene therapies to patients around the world. In Project 3 (An), we will test another important aspect in a total of 6 NHP: the ability to precisely regulate the levels of gene-modified HSPCs and their progeny ex vivo and in vivo. Each of the NHP Core's project-specific functions will be assessed with an eye towards the clinic, in close consultation with our longstanding partners in Project 4 (Symonds). The goals set forth by the NHP Core are to implement each of the NHP studies described above, produce gene-modified NHP HSPC products using potent lentiviral vectors, and to provide supportive care for animals in each project, both following HSPC gene therapy and infection with HIV-like viruses. Each of the four projects in our consortium are highly complementary. We will bridge large animal studies overseen by each project, contribute meaningfully to discussions regarding synergies between projects, and evaluate new and promising therapies as they emerge.

核心 C：项目总结/摘要造血干细胞和祖细胞 (HSPC) 移植是唯一已知的 HIV-1 病例的基础然而，在这项开创性的临床案例研究 12 年后，功能性治愈有了显着的改善。需要将此案例研究应用于更广泛的艾滋病病毒感染者，这是我们的总体目标。 U19联盟将确定安全有效地修改患者自身HSPC以抵抗的候选策略 HIV感染后，同时增强其识别和消灭感染细胞的能力。灵长类动物（NHP）核心将在组织每个人提出的方法的临床前方面发挥核心作用我们小组的项目，重点关注最适合未来试验的翻译相关功能在项目 1（厨房）中，我们将生成一系列 12 个 NHP，并用自体、这些细胞将表达一种有前途的病毒特异性免疫效应分子，称为基因修饰的 HSPC。 CD4CAR 与其他有前景的疗法（例如广泛中和抗体（bNAb））相结合，以及 CD4CAR 修饰的 HSPC 后代，结合 bNAb 和疫苗特异性疫苗。在项目 2（Morizono）中，我们代表了一种强大且协同的方法来实现目标病毒持久性。将重点关注基因修饰 HSPC 而不将其从体内移除的方法，总共研究 9 NHP。所谓的“体内递送”方法将显着增强抗HIV基因的适用性。在项目 3 (An) 中，我们将测试总共 6 个 NHP 的另一个重要方面：能够在体外和体内精确调节基因修饰的 HSPC 及其后代的水平。 NHP 核心项目特定功能的评估将着眼于诊所，并进行密切协商与我们在项目 4（Symonds）中的长期合作伙伴一起 NHP 核心制定的目标是实施。上述每项 NHP 研究均使用强效慢病毒生产基因修饰的 NHP HSPC 产品载体，并为每个项目中的动物提供支持性护理，包括 HSPC 基因治疗和我们联盟的四个项目都是高度互补的。桥接每个项目监督的大型动物研究，为有关协同效应的讨论做出有意义的贡献项目之间，并在出现新的和有前途的疗法时对其进行评估。