Primate Core

摘要 造血干细胞移植(HSCT)是目前已知的唯一一种持久的治疗方法。 柏林患者的HIV-1缓解/功能治愈，最近伦敦患者也是如此。 这两名患者都接受了相关恶性肿瘤的治疗；需要显著的改善才能 将这些案例研究应用于更广泛的艾滋病毒个体。我们的U19财团专注于 增强基因编辑的HSPC的抗HIV功能，并安全地将这些细胞移植到体内。非人类 灵长类(NHP)核心将在组织由我们的每个项目提出的所有大型动物研究方面发挥核心作用 重点放在最适合未来患者试验的方法上。我们将与 项目3/Cannon和项目4/Kiem采用优化的协议来编辑HSPC，重点是 最大化同源定向修复(HDR)。在项目1/Scadden、项目2/Magenta和项目4 Kiem中，我们 将在总共40个国家健康保险计划中应用和评估这一方法。每只动物将接受自体的、经HDR修饰的 包含条形码的、基因编辑的CCR5等位基因(∆CCR5)的HSPC，或包含 CD4CAR∆CCR5和eCD4-Ig∆CCR5 HSPC。为了评估我们策略的有效性，我们将模拟HIV 使用猿猴/人类免疫缺陷病毒(SHV)感染NHP。在一项研究设计中，24只动物将被 移植经过基因编辑的HSPC，然后进行SIV攻击以量化对病毒的保护 收购。为了模拟HIV的持久性，16只动物将被感染SIV并被抗逆转录病毒抑制 HSPC移植前的治疗(ART)。康复后，动物将被从艺术品中移除，而 SIV反弹的动力学和幅度将与未移植的对照动物进行比较。除了……之外 CD4CAR∆CCR5和eCD4-Ig∆CCR5 HSPC，动物也将接受非遗传毒性调节(Ngc) 方案由项目2/Magenta设计，骨髓冷冻剂(BMC)由项目1/Scadden开发。 这些额外的治疗方法将分别显著提高我们方法的安全性和有效性。这个 NHP Core将实施上述两种SHIV研究设计，生成经过基因编辑的NHP HSPC 产品，并在HSPC基因治疗和SHV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关于协同效应的讨论做出有意义的贡献 在项目之间，以及选择最佳组合以推进早期临床研究。

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.