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: 6162552
• 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/6162552
• 关键词: SCID mouse; cytokine receptors; dogs; gene expression; gene mutation; gene therapy; hematopoietic stem cells; human genetic material tag; human tissue; immunofluorescence technique; immunopathology; interleukin 2; newborn human (0-6 weeks); nonhuman therapy evaluation; severe combined immunodeficiency; sex linked trait; tissue /cell culture; transfection /expression vector; umbilical cord

The gamma chain gene of the IL-2 receptor (IL2RG) has been identified as responsible for X-linked severe combined immunodeficiency (SCID), 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 HLA matched donors in over 2/3 of cases, poor post-transplant B cell function, and late T cell loss. In vivo negative selection against cells expressing a mutant IL2RG makes X-linked SCID a promising candidate for therapy with retrovirally transduced autologous repopulating stem cells. This strategy was pursued by comparing different retrovirus constructs for titer, gamma chain expression in transduced 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 in SCID mice. These experiments have shown significant cell surface expression of the gamma chain protein 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. Canine spontaneous gamma chain mutations resulting in SCID dogs are being studied in collaboration with Paula Henthorn, at the U. of PA School of Vet. Med. Marking experiments in normal dogs pretreated with cytokines and sublethal irradiation have achieved unprecidented levels of long-term expression of human gamma chain for over one year. Follow-up experiments in SCID dogs are planned.

IL-2受体（IL2RG）的γ链基因已被确定为