GENE TRANSFER FOR THERAPY OF IL 2 RECEPTOR GAMMA CHAIN DEFICIENT X LINKED SCID

用于治疗 IL 2 受体伽玛链缺陷型 X 连锁 SCID 的基因转移

• 批准号: 5203423
• 负责人: J M PUCK
• 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/5203423
• 关键词: Retroviridae; child (0-11); cytokine receptors; gene expression; gene mutation; gene therapy; human genetic material tag; human subject; human tissue; immunofluorescence technique; interleukin 2; severe combined immunodeficiency; sex linked trait; transfection /expression vector

The gamma chain gene of the interleukin-2 receptor (IL2RG) has been identified as the gene responsible for X-linked severe combined immunodeficiency (SCID). This is the most common form of human SCID. The only available lifesaving treatment at the present time is bone marrow transplantation, but drawbacks of this procedure include the lack of an HLA matched donor in over 2/3 of cases and poor post-transplant B cell function, primarily due to non-engraftment of B cells. The previously proven negative selection against cells expressing a mutant IL2RG, resulting in skewed X chromosome inactivation in female carriers, makes X-linked SCID a promising candidate for therapy with retrovirally transduced autologous repopulating stem cells. This strategy is being pursued first by comparing different retrovirus constructs for titer, gamma chain expression in transduced mouse and human cell lines, correction of the functional defect in EBV-B cell lines from SCID-affected patients with defined IL2RG defects, and monitoring the development of cord blood stem cells transduced with IL2RG retroviruses into lymphocytes in SCID and SCID/NOD mice. These experiments have shown significant cell surface expression of the gamma chain protein by immunofluorescence in previously deficient cell lines from SCID patients. The availability of a large panel of patient cell lines will permit evaluation of potential dominant negative mutations. SCID patients prenatally diagnosed with defined IL2RG mutations have had their cord blood collected at birth for experimental transduction and evaluation of lymphocytogenesis.

白介素2受体(IL2RG)的伽马链基因已经被 被鉴定为X连锁重症合并的致病基因 免疫缺陷(SCID)。这是人类SCID最常见的形式。 目前唯一可用的挽救生命的治疗方法是骨 骨髓移植，但这一程序的缺点包括缺乏 超过2/3的病例中存在人类白细胞抗原相合的供者，且移植后B细胞质量差 细胞功能，主要是由于B细胞不能植入。这个 先前证实的针对表达突变的细胞的负选择 IL2RG，导致女性携带者X染色体倾斜失活， 使X连锁SCID成为逆转录病毒治疗的有前途的候选者 转导的自体再生干细胞。这一战略正在被 首先通过比较不同逆转录病毒结构的滴度来进行研究， 伽马链在转导的小鼠和人类细胞系中的表达， EBV-B细胞株功能缺陷的矫治 有明确IL2RG缺陷的SCID患者，并监测 IL2RG逆转录病毒转导脐血干细胞的研究进展 转化为SCID和SCID/NOD小鼠的淋巴细胞。这些实验表明 伽马链蛋白在细胞表面的显著表达 来自SCID患者的先前缺陷细胞系的免疫荧光。 一大批患者细胞系的可用将允许 潜在显性负性突变的评估。SCID患者 在产前被诊断为明确的IL2RG突变 出生时采集血液用于实验转导和评估 淋巴细胞生成。