Nonhuman Primate Core

非人类灵长类核心

• 批准号: 10160817
• 负责人: HANS-PETER KIEM
• 金额: $ 89.79万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/10160817
• 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; in vivo; 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

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：项目摘要/摘要 造血干细胞和祖细胞（HSPC）的移植是HIV-1唯一已知的病例 功能治疗。但是，在这项开创性的临床案例研究之后的12年中，大大改善是 为了将此案例研究应用于更广泛的HIV+个体所需。我们的总体目标 U19财团是确定候选策略，以安全有效地修改患者自己的HSPC以抵抗 艾滋病毒感染，仅增强了他们识别和破​​坏感染细胞的能力。非人类 灵长类动物（NHP）核心将在组织每种方法提出的方法的临床前方面发挥核心作用 我们小组的项目，保持着专注于翻译相关功能，这些功能最适合以后的试验 在患者中。在项目1（厨房）中，我们将生成一系列12个NHP，这些NHP被自体移植， 基因改性的HSPC。这些细胞将表达有希望的病毒特异性免疫效应子分子 CD4CAR与其他有希望的疗法结合使用，例如广泛中和抗体（BNAB）和 治疗疫苗。 CD4CAR修饰的HSPC后代，结合BNAB和疫苗特异性 细胞代表了针对病毒持久性的强大而协同的方法。在项目2（Morizo​​no）中，我们 将重点介绍基因修饰HSPC的方法，而无需将其从体内移除，总共研究了9个 NHP。所谓的“体内递送”方法将显着提高抗HIV基因的适用性 对世界各地的患者进行疗法。在项目3（AN）中，我们将在总共6 NHP中测试另一个重要方面： 精确调节基因改性HSPC的水平及其后代和体内的能力。每个 在密切咨询中，将对NHP Core的项目特定功能进行评估 与我们在项目4（Symonds）的长期合作伙伴一起。 NHP核心设定的目标是实施 上面描述的每项NHP研究，使用有效的慢病毒产生了基因修饰的NHP HSPC产物 载体，并为每个项目中的动物提供支持，包括HSPC基因疗法和 感染HIV样病毒。我们财团中的四个项目中的每个项目都是高度互补的。我们将 桥梁由每个项目监督的大型动物研究，对协同的讨论有意义地贡献 在项目之间，评估新的和承诺疗法的出现。