Nongenotoxic conditioning for HIV cure transplantation approaches

HIV治愈移植方法的非基因毒性调理

• 批准号: 9891829
• 负责人: Glen D Raffel
• 金额: $ 51.42万
• 依托单位: MAGENTA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9891829
• 关键词: AIDS/HIV problem; Acute; Address; Adopted; Allogenic; Animals; Antibody-drug conjugates; Antiviral Agents; Autologous; Autologous Transplantation; BLT mice; Berlin; CCR5 gene; Cell Transplantation; Cells; Chimerism; Chronic; Clinical Trials; Collaborations; Complication; Development; Disease; Donor person; Dose; Engineering; Engraftment; Environment; Frequencies; Gene-Modified; Generations; Genes; Genetic Recombination; Goals; HIV; HIV Infections; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; Hospitalization; Immune; Immune system; Immunity; Immunologic Deficiency Syndromes; Infection; Intervention; Lead; Life; London; Macaca mulatta; Malignant Neoplasms; Marrow; Methods; Modeling; Morbidity - disease rate; Non-Malignant; PTPRC gene; Patients; Population; Process; Property; Proto-Oncogene Protein c-kit; Reagent; Regimen; Resistance; Resources; Rhesus; Schedule; Stem cell transplant; T-Lymphocyte; Technology; Toxic effect; Transplantation; Viral reservoir; Virus; Withdrawal; Work; antiretroviral therapy; base; cell regeneration; cellular development; chemokine receptor; chimeric antigen receptor; clinical application; conditioning; disorder control; engineered stem cells; experience; graft vs host disease; immune reconstitution; improved; neutralizing antibody; novel; preclinical development; preservation; simian human immunodeficiency virus; stem cells; success

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.

抽象的 使用造血干细胞（HSC）移植的HIV治愈 “柏林患者”的经验。伦敦和杜塞尔多夫患者的最新结果非常 鼓励并有可能增强移植作为艾滋病毒的治疗方法。仍然是一个挑战 降低造血干细胞移植的复杂性，以便更容易采用它 在不急性生命的环境中，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，从而消除了移植的破坏性并发症 相对于宿主疾病，并解决了同种异体CCR5 ∆32/∆32供体的有限可用性。然而， “调理”使干细胞能够植入骨髓是有毒的，需要资源 目前正在实践的密集住院。 我们旨在开发利用抗体药物结合物的非核调理（NGC） （ADC）特异性靶向和微妙的造血细胞群体作为利基市场保留 毒性降低的方法。通过研究HSPC特异性的ADC（抗CD117 靶向）或更广泛的免疫离发（抗CD45靶向），我们旨在确定最佳 NGC在免疫缺陷中实现有效的HSC移植的策略。我们将结合我们的 基于ADC的调节，具有自体基因修饰细胞移植的动物感染 识别具有翻译价值的潜在客户策略的模型。该项目的具体目的是： 特定目标1.优化用抗CD117 ADC处理NHP的剂量和时间表以实现 耐用的供体嵌合。 特定目标2。优化用抗CD45 ADC处理NHP的剂量和时间表以实现 耐用的供体嵌合。 特定目标3。确定非核调节和基因修饰的HSC是否 移植能够控制感染动物的疾病。 如果成功，该项目将提供特定的干预措施，以降低基因的障碍 修饰的HSC移植作为治愈艾滋病毒/艾滋病的方法。