Primate Core

摘要 造血干细胞移植（HSCT）是目前唯一已知的可持久治疗的治疗方法 HIV-1缓解/功能性治愈，如柏林患者和最近的伦敦患者所示。 这两例患者均接受了相关恶性肿瘤的治疗;需要显著改善， 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 增强基因编辑的HSPC的抗HIV功能，并在体内安全地移植这些细胞。非人 灵长类动物（NHP）核心将在组织我们的每个项目提出的所有大型动物研究中发挥核心作用。 小组，重点是最适合未来患者试验的方法。我们将与 项目3/Cannon和项目4/Kiem采用优化方案进行基因编辑HSPC，重点是 最大化同源定向修复（HDR）。在项目1/Scadden、项目2/洋红和项目4 Kiem中，我们 将在总共40个国家卫生方案中应用和评估这一方法。每只动物将接受自体的、HDR修饰的 含有条形码化的基因编辑的CCR 5等位基因（CCR 5）的HSPC，或含有CCR 5的“三合一”产物， CD 4 CAR介导CCR 5和eCD 4-IG介导CCR 5 HSPC。为了评估我们的策略的有效性，我们将模拟艾滋病毒 NHP感染，使用猿猴/人类免疫缺陷病毒（SHIV）。在一项研究设计中，将有24只动物 移植基因编辑的HSPC，然后进行SHIV攻击以量化针对病毒的保护 采集为了模拟HIV持续性，16只动物将感染SHIV并通过抗逆转录病毒药物抑制 在HSPC移植之前进行ART治疗。恢复后，将动物从ART中移除， 将SHIV反弹的动力学和幅度与未移植的对照动物进行比较。除了 CD 4 CAR-β CCR 5和eCD 4-IG β CCR 5 HSPC，动物也将接受非遗传毒性预处理（NGC） 由Project 2/洋红设计的方案和由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。的 NHP Core将实施上述两种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感染后提供支持性护理。大型动物 我们代表每个项目指导的研究将对有关协同作用的讨论作出有意义的贡献 在项目之间，并选择最佳组合以进行早期临床研究。

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.