Primate Core

灵长类核心

基本信息

批准号：
10163908
负责人：
HANS-PETER KIEM
金额：
$ 50.71万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
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：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10163908
关键词：
Acquired Immunodeficiency Syndrome Alleles Animals Autologous Bar Codes Berlin Biological Assay Bone Marrow CCR5 gene California Caring Case Study Cell Transplantation Cells Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Communicable Diseases Control Animal Data Development Disease remission Dose Engraftment Fumarates Future Gene-Modified Genes HIV HIV Infections HIV-1 Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Immunity Individual Infection Kinetics Letters London Louisiana Macaca mulatta Malignant Neoplasms Measures Methods Modeling Modification Oregon Patients Persons Phase Plasma Play Population Positioning Attribute Pre-Clinical Model Primates Prior Therapy Prodrugs Protocols documentation Public Health Publishing Recovery Regimen Research Research Design Research Personnel Role Rosaniline Dyes Safety Sampling Source Stem cell transplant Study models Supportive care Tenofovir Therapeutic Tissues Transplantation Vaccine Therapy Viral Load result Viral reservoir Virus Virus Replication Washington Work antiretroviral therapy base clinically relevant cohort conditioning cryogel design efficacy evaluation emtricitabine engineered stem cells experience experimental study gene function gene therapy in vivo latent infection model development nonhuman primate novel novel strategies peripheral blood pinacolyl methylphosphonic acid post-transplant repaired simian human immunodeficiency virus success synergism therapeutic genome editing translational medicine viral rebound

项目摘要

ABSTRACT Hematopoietic stem cell transplantation (HSCT) is currently the only known treatment that has resulted in durable HIV-1 remission/functional cure as shown in the Berlin Patient, and most recently also in the London Patient. Both of these patients were treated for associated malignancies; significant improvements are needed in order to apply these case studies to a broader population of HIV+ individuals. Our U19 consortium is focused on enhancing the anti-HIV function of gene-edited HSPC, and safely engrafting these cells in vivo. The Nonhuman Primate (NHP) Core will play a central role in organizing all large animal studies proposed by each project in our group, with a focus on approaches that are most suitable for future trials in patients. We will work closely with Project 3/Cannon and Project 4/Kiem to adapt an optimized protocol to gene edit HSPCs, with a focus on maximizing homology directed repair (HDR). In Project 1/Scadden, Project 2/Magenta, and Project 4 Kiem, we will apply and evaluate this approach in a total of 40 NHPs. Each animal will receive autologous, HDR-modified HSPCs containing either barcoded, gene-edited CCR5 alleles (∆CCR5), or a “three for one” product containing both CD4CAR∆CCR5 and eCD4-Ig∆CCR5 HSPCs. To evaluate the efficacy of our strategy, we will model HIV infection in NHPs, using simian/human immunodeficiency virus (SHIV). In one study design, 24 animals will be transplanted with gene edited HSPCs, followed by SHIV challenge to quantify protection against virus acquisition. To model HIV persistence, 16 animals will be infected with SHIV and suppressed by antiretroviral therapy (ART) prior to HSPC transplantation. Following recovery, animals will be removed from ART, and the kinetics and magnitude of SHIV rebound will be compared to untransplanted control animals. In addition to CD4CAR∆CCR5 and eCD4-Ig∆CCR5 HSPCs, animals will also receive a nongenotoxic conditioning (NGC) regimen designed by Project 2/Magenta, and bone marrow cryogel (BMC) developed by Project 1/Scadden. These additional treatments will substantially enhance the safety and efficacy of our approach, respectively. The NHP Core will implement both of the SHIV study designs described above, produce gene edited NHP HSPC products, and provide supportive care following HSPC gene therapy and infection with SHIV. The large animal studies we direct on behalf of each project will contribute meaningfully to discussions regarding synergies between projects, and selection of the best combinations to forward to early phase clinical studies.

抽象的造血干细胞移植（HSCT）目前是唯一已知的耐用的治疗方法 HIV-1缓解/功能治疗如柏林患者所示，最近也是伦敦患者。两名患者都需要进行相关的恶性肿瘤；将案例研究应用于更广泛的艾滋病毒+个体。增强基因编辑的HSPC的抗HIV功能，并在非人类中安全地使用英语细胞灵长类动物（NHP）核心将在组织每个项目中提出的所有大型动物研究中发挥核心作用小组，重点是最适合于Patation试验的方法。项目3/CANNON和项目4/KIEM，以适应基因编辑HSPC的优化方案，重点是最大化同源性维修（HDR）。将以40个NHP的方式申请并评估Apploach。 HSPC遏制了条形码，基因编码的CCR5等位基因（∆CCR5），或一个包含的“三个”产品 CD4CARΔCCR5和ECD4-IGΔCCR5HSPC评估我们策略的功效，我们将建模HIV NHP中的感染，使用猿猴/人类免疫缺陷病毒（SHIV）。用基因编辑的HSPC移植，然后进行SHIB挑战以量化对病毒的保护获得艾滋病毒持久性的收购，16只动物会通过抗逆转录病毒抑制在恢复后HSPC透明之前的治疗（ART），动物将从ART中撤回除了未发育的对照动物，还将将动力学和射精的动力学和大幅度进行比较 CD4CARΔCCR5和ECD4-IGΔCCR5HSPC，动物还将接受非核调理（NGC）由项目2/Magenta设计的方案和由项目1/Scadden开发的骨髓冷冻盖尔（BMC）。这些其他治疗方法将大大提高我们方法的安全性和功效 NHP Core将实施上述SHIV研究设计，生产基因编辑的NHP HSPC 产品，并在HSPC基因治疗疗法后提供支持我们代表每个项目指导的研究，有助于有关协同作用的讨论在项目之间以及选择最佳组合以转到早期临床研究。