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.

摘要