Gene Transfer into Hematopoietic Stem Cells

基因转移至造血干细胞

• 批准号: 6555998
• 负责人: Fabio Candotti
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 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/6555998
• 关键词: AIDS; AIDS /HIV diagnosis; HIV infections; blood disorder; blood disorder chemotherapy; bone marrow; cell differentiation; clinical research; cord blood; gene therapy; genetic manipulation; genetic regulation; hematopoietic stem cells; hematopoietic tissue transplantation; human subject; laboratory mouse; leukemia; sheep; stem cell transplantation; thalassemia; tissue /cell culture; transplantation immunology

Genetic manipulation of hematopoietic stem cells has the potential to treat a variety of human diseases. However, gene transfer into stem cells of large animal models and humans has thus far proven to be difficult and inefficient. By gaining insights into the biology of the hematopoietic stem cell, this project aims to improving the efficiency of gene transfer/correction of this rare and elusive target cell. Potential applications of this technology include therapeutic approaches for common blood disorders (e.g. thalassemia), malignancies (e.g. leukemia) and infectious diseases of the blood cells, such as HIV-1 infection/AIDS. We have established in vitro and in vivo animal models of human hematopoiesis using human hematopoietic progenitors obtained from cord blood or bone marrow of volunteer donors. These cells are cultured and genetically engineered in vitro, and then allowed to differentiate into mature cell lineages in vitro (using colony forming unit or T cell differentiation assays) or in vivo, using mouse or sheep animal models. These experiments allow testing vectors and gene transfer conditions that efficiently target human hematopoietic cells and determination of the capability of engineered cells to engraft and/or differentiate into mature progenies.

造血干细胞的遗传操纵具有治疗多种人类疾病的潜力。然而，迄今为止，基因转移到大型动物模型和人类的干细胞中是困难和效率低下的。通过深入了解造血干细胞的生物学，该项目旨在提高基因转移/纠正/校正该罕见且难以捉摸的靶细胞的效率。这项技术的潜在应用包括常见血液疾病（例如，thalassya），恶性肿瘤（例如白血病）和血细胞感染性疾病（例如HIV-1感染/艾滋病）的治疗方法。我们已经使用从志愿供体的脐带血或骨髓获得的人类造血祖细胞建立了人类造血的体外和体内动物模型。这些细胞在体外进行培养和基因设计，然后在体外（使用菌落形成单元或T细胞分化测定法）或使用小鼠或绵羊动物模型分化为成熟的细胞谱系。这些实验允许测试载体和基因转移条件有效地靶向人类造血细胞，并确定工程细胞植入和/或分化为成熟后代的能力。