Nongenotoxic conditioning for HIV cure transplantation approaches

摘要 使用造血干细胞（HSC）移植治疗HIV得到了以下方面的支持： “柏林病人”的经历。最近来自伦敦和杜塞尔多夫患者的结果非常 鼓励并可能支持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，使其更容易被采用 在不严重威胁生命的环境中，如慢性艾滋病。基因编辑将 使自体细胞移植成为可能，从而消除了移植的毁灭性并发症， 抗宿主疾病的研究，并解决了同种异体CCR 5 β 32/β 32供体的有限可用性。然而，在这方面， 使干细胞能够植入骨髓的“条件作用”具有高度毒性，需要资源 目前实行的集中住院治疗。 我们的目标是开发利用抗体药物偶联物的非遗传毒性调节（NGC （ADC）特异性靶向和消耗造血细胞群体作为小生境保留， 降低毒性的方法。通过研究HSPC特异性ADC（抗CD 117 靶向）或更广泛的免疫耗竭（抗CD 45靶向），我们的目标是确定最佳的 NGC策略使免疫缺陷患者能够进行有效的HSC移植。我们将联合收割机 在动物感染中使用自体基因修饰的细胞移植的基于ADC的预处理 模型来确定具有转化价值的领先战略。该项目的具体目标是： 具体目标1.优化抗CD 117 ADC治疗NHP的剂量和方案， 持久的供体嵌合体 具体目标2。优化抗CD 45 ADC治疗NHP的剂量和方案， 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 移植使得能够在受感染动物中控制疾病。 如果成功，该项目将提供具体的干预措施，可以降低基因治疗的障碍。 改良HSC移植作为治疗HIV/AIDS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.