Primate Core

灵长类核心

基本信息

批准号：
10601066
负责人：
HANS-PETER KIEM
金额：
$ 133.35万
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/10601066
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 Dedications Development Disease remission Dose Engraftment Experimental Designs 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 clinically relevant cohort conditioning cryogel design efficacy evaluation emtricitabine engineered stem cells experience gene function gene therapy improved in vivo in vivo engraftment latent infection manufacture model development nonhuman primate novel novel strategies peripheral blood pinacolyl methylphosphonic acid post-transplant repaired simian human immunodeficiency virus success synergism 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）是目前唯一已知的可产生持久疗效的治疗方法。 HIV-1 缓解/功能性治愈，如柏林患者和最近伦敦患者的情况所示。这两名患者都接受了相关恶性肿瘤的治疗；需要显着改善才能达到目的。将这些案例研究应用于更广泛的 HIV+ 人群。我们的 U19 联盟专注于增强基因编辑 HSPC 的抗 HIV 功能，并将这些细胞安全地移植到非人类体内。灵长类动物 (NHP) 核心将在组织我们每个项目提出的所有大型动物研究方面发挥核心作用我们将与小组密切合作，重点关注最适合未来患者试验的方法。项目 3/Cannon 和项目 4/Kiem 采用优化的方案来编辑 HSPC，重点是在项目 1/Scadden、项目 2/Magenta 和项目 4 Kiem 中，我们最大化同源定向修复 (HDR)。将在总共 40 只 NHP 中应用并评估这种方法，每只动物将接受经过 HDR 修饰的自体移植。 HSPC 含有条形码、基因编辑的 CCR5 等位基因 (ΔCCR5)，或“三合一”产品，其中含有 CD4CARΔCCR5 和 eCD4-IgΔCCR5 HSPC 为了评估我们策略的有效性，我们将对 HIV 进行建模。在一项研究设计中，将使用猿猴/人类免疫缺陷病毒 (SHIV) 检测 NHP 感染。移植基因编辑的 HSPC，然后进行 SHIV 挑战以量化对病毒的保护为了模拟 HIV 持续性，16 只动物将感染 SHIV 并被抗逆转录病毒药物抑制。 HSPC 移植前接受治疗 (ART) 恢复后，动物将不再接受 ART，并且 SHIV 反弹的动力学和幅度将与未移植的对照动物进行比较。 CD4CARΔCCR5 和 eCD4-IgΔCCR5 HSPC，动物还将接受非基因毒性调节 (NGC) 由 Project 2/Magenta 设计的治疗方案和由 Project 1/Scadden 开发的骨髓冷冻凝胶 (BMC)。这些额外的治疗将分别大大提高我们方法的安全性和有效性。 NHP Core 将实施上述两项 SHIV 研究设计，生产基因编辑的 NHP HSPC 产品，并在 HSPC 基因治疗和 SHIV 感染后提供支持护理。我们代表每个项目指导的研究将为有关协同效应的讨论做出有意义的贡献项目之间，并选择最佳组合以推进早期临床研究。