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) 移植治愈艾滋病毒得到了以下机构的支持 “柏林患者”的经历最近来自伦敦和杜塞尔多夫患者的结果非常好。 鼓励并可能促进移植作为治疗艾滋病毒的方法仍然是一个挑战。 降低造血干细胞移植的复杂性，使其更容易被采用 在没有严重危及生命的环境中，例如慢性艾滋病毒，基因编辑将会。 进行自体细胞移植，从而消除移植的破坏性并发症 对抗宿主疾病并解决同种异体 CCR5 Δ32/Δ32 供体的有限可用性。 使干细胞植入骨髓的“调节”具有剧毒且需要资源 目前实行的重症住院治疗。 我们的目标是开发利用抗体药物偶联物的非基因毒性调节 (NGC) （ADC）专门针对并消耗造血细胞群作为利基保留 通过研究 HSPC 特异性的 ADC（抗 CD117）。 靶向）或更广泛的免疫耗竭（抗 CD45 靶向），我们的目标是确定最佳的 我们将结合我们的 NGC 战略，实现免疫缺陷患者的高效 HSC 移植。 基于 ADC 的自体基因修饰细胞移植调理动物感染 确定具有转化价值的主导策略的模型 该项目的具体目标是： 具体目标1.优化抗CD117 ADC治疗NHP的剂量和方案，以实现 持久的供体嵌合现象。 具体目标2.优化抗CD45 ADC治疗NHP的剂量和方案，以实现 持久的供体嵌合现象。 具体目标3.确定是否非基因毒性调理和基因修饰HSC 移植能够控制受感染动物的疾病。 如果成功，该项目将提供具体的干预措施，降低基因障碍 改良HSC移植作为治疗HIV/AIDS的方法。