Nongenotoxic conditioning for HIV cure transplantation approaches

摘要 使用造血干细胞(HSC)移植治愈艾滋病毒得到了来自 《柏林病人》的经历。伦敦和杜塞尔多夫的患者最近的结果非常好 鼓励并有可能支持将移植作为治疗艾滋病毒的方法。仍然存在的挑战是 降低造血干细胞移植的复杂性，以便更容易采用 在不是严重威胁生命的环境中，例如慢性艾滋病毒疾病。基因编辑将 使自体细胞移植成为可能，从而消除移植的破坏性并发症 针对宿主疾病，并解决同种异体CCR5∆32/∆32捐赠者的有限可获得性。然而， 使干细胞能够植入骨髓的“条件调节”是剧毒的，需要资源。 按照目前的做法进行重症住院治疗。 我们的目标是开发利用抗体药物结合物的非遗传毒性调节(NGC)。 (ADC)专门针对和消耗造血细胞群体，作为一种利基节约 方法降低毒性。通过调查HSPC特异性的ADC(抗CD117 靶向)或更广泛的免疫消耗(抗CD45靶向)，我们的目标是确定最佳的 使免疫缺陷患者进行高效的造血干细胞移植的NGC策略。我们将把我们的 自体基因修饰细胞移植在动物感染中基于ADC的调节作用 确定具有转换价值的领先战略的模型。该项目的具体目标是： 具体目的1.优化抗CD117 ADC治疗NHP的剂量和方案，以实现 持久的供体嵌合体。 具体目标2.优化抗CD45 ADC治疗NHP的剂量和方案，以实现 持久的供体嵌合体。 具体目标3.确定非遗传毒性调节和基因修饰的HSC 移植使受感染的动物能够控制疾病。 如果成功，这个项目将提供可以降低基因障碍的具体干预措施。 改良的造血干细胞移植作为治疗艾滋病毒/艾滋病的方法。

Abstract The cure of HIV using hematopoietic stem cell (HSC) transplant is supported from the experience of the `Berlin patient'. Recent results from patients in London and Düsseldorf are very encouraging and potentially bolster transplant as a cure for HIV. What remains a challenge is to reduce the complexity of hematopoietic stem cell transplant so that it may be more readily adopted in settings that are not acutely life threatening such as chronic HIV disease. Gene editing will make autologous cell transplant possible thereby eliminating the devastating complication of graft versus host disease and address limited availability of allogeneic CCR5 ∆32/∆32 donors. However, `conditioning' to enable stem cells to engraft the marrow is highly toxic and requires resource intensive hospitalization as currently practiced. We aim to develop nongenotoxic conditioning (NGC) that leverages antibody drug conjugates (ADCs) to specifically target and deplete hematopoietic cell populations as a niche sparing method with reduced toxicity. By investigating ADCs that are HSPC-specific (anti-CD117 targeting) or more broadly immune depleting (anti-CD45 targeting), we aim to identify the optimal NGC strategy for enabling efficient HSC transplant in immunodeficiencies. We will combine our ADC-based conditioning with autologous gene-modified cell transplants in animal infection models to identify a lead strategy with translational value. The specific aims of this project are: Specific aim 1. Optimize the dose and schedule of treating NHP with anti-CD117 ADC to achieve durable donor chimerism. Specific aim 2. Optimize the dose and schedule of treating NHP with anti-CD45 ADC to achieve durable donor chimerism. Specific aim 3. Determine whether nongenotoxic conditioning and gene-modified HSC transplant enable disease control in infected animals. If successful, this project will provide specific interventions that can lower the barrier for gene modified HSC transplantation as an approach to cure HIV/AIDS.