HEMATOPOIETIC STEM CELLS TRANSPLANTATION

造血干细胞移植

• 批准号: 6359638
• 负责人: Robertson Parkman
• 金额: $ 18.55万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6359638
• 关键词: Retroviridae; adenosine deaminase; adolescence (12-20); autologous transplantation; biotechnology; bone marrow; bone marrow transplantation; child (0-11); clinical research; cord blood; enzyme deficiency; enzyme therapy; flow cytometry; gene expression; gene therapy; hematopoietic stem cells; human subject; human therapy evaluation; radiation immunosuppression; severe combined immunodeficiency; sex linked trait; stem cell transplantation; transfection /expression vector

Project 4 consists of three clinical protocols. Protocol 1 is an assessment of two new murine retroviral vectors to transduce the HSC of patients with adenosine deaminase (ADA) deficiency. The two second generation vectors both contain promoters, which based upon pre-clinical data, will support ADA gene expression in resting peripheral blood T lymphocytes, the major problem that we have identified in our previous ADA clinical gene therapy trial. Both bone marrow and cord blood HSC will be transduced. Protocol 2 will evaluate patients with common gamma chain (X-linked SCID) deficiency with a MND containing retroviral based vector using HSC of either bone marrow or cord blood origin. The lack of alternative enzyme replacement therapy will permit the evaluation of HSC transduction and a selective advantage for T lymphoid and NK progeny within 3-6 months. Protocol 3 is an evaluation of the capacity of FACS purified bone marrow HSC (CD34+, CD38-, gamma/c) to lymphohematopoietically reconstitute patients who have received myeloablative doses of irradiation. After successful reconstitution with the purified HSC, we will evaluate the ability of lentivirus based vectors to transduce HSC and the clonality of post-transplant lymphohematopoiesis. The three Protocols utilize improved transduction conditions and vectors derived from prior SCOR supported research. It is anticipated that additional clinical protocols and modifications based upon ongoing pre-clinical research will occur during the next SCOR funding period.

项目4由三个临床方案组成。协议1是对两个新的鼠逆转录病毒载体的评估，以转导腺苷脱氨酶（ADA）缺乏症患者的HSC。第二代载体都包含启动子，基于临床前数据，将支持静息外周血T淋巴细胞中的ADA基因表达，这是我们在先前的ADA临床基因治疗试验中发现的主要问题。骨髓和脐带血HSC都将被转导。方案2将使用骨髓或脐带血来源的HSC评估含有基于逆转录病毒的载体的MND的常见伽马链（X连锁SCID）缺陷患者。缺乏替代酶替代疗法将在3-6个月内评估HSC转导和T淋巴后后代的选择性优势。方案3是对FACS纯化的骨髓HSC（CD34+，CD38-，γ/C）的能力评估，以对接受骨髓性辐照剂量的淋巴细胞学重新构成患者。成功地使用纯化的HSC重组后，我们将评估基于慢病毒的载体转导HSC和移植后淋巴结肿瘤的克隆性的能力。这三个方案利用了改进的转导条件和从先前的SCOR支持的研究中得出的向量。可以预计，基于持续的临床前研究将在下一个SCOR资金期间进行其他临床方案和修改。