Retroviral Vectors for Gene Therapy of HIV-1 Infection

用于 HIV-1 感染基因治疗的逆转录病毒载体

• 批准号: 6534092
• 负责人: ROGER J POMERANTZ
• 金额: $ 24.73万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6534092
• 关键词: AIDS therapy; HIV infections; Retroviridae; SCID mouse; T lymphocyte; antiAIDS agent; clinical research; gene delivery system; gene therapy; genetic transduction; human immunodeficiency virus 1; human tissue; laboratory mouse; laboratory rat; method development; neurons; polymerase chain reaction; tissue mosaicism; transfection /expression vector

DESCRIPTION (Provided by the applicant): In the past decade, the research in Dr. Domburg?s laboratory has been focused on the development of cell-type-specific retroviral vectors, derived from the avian reticuloendotheliosis viruses, spleen necrosis virus, SNV, and reticuloendotheliosis virus strain A, REV-A. Cell-type-specific retroviral vector particles have been developed, which enable highly efficient gene transduction into cells of the human hematopoietic system. Modifications in the matrix (MA) protein of SNV and REV-A enabled gene transduction of quiescent hematopoietic cells. Using SCID mice and subcutaneous tumors as a model, our preliminary data suggest that a target cell specific gene delivery can be obtained in vivo with SNV-derived retroviral vectors implanted in Theracyte immunoisolation devices. We will continue to use this current model system to further evaluate (i) the duration and efficiency of the gene transfer and (ii) to establish selected packaging cells lines selected and optimized for efficient in vivo gene delivery through Theracyte implantation bags (Specific Aim #1). New vector systems will be developed which will enable to expand our studies with Theracyte immunoisolation devices using (i) hu- PBL-SCID mice and human hematopoietic cells as targets and (ii) mice models for gene delivery into neuronal cells. Helper cells will be implanted in Theracyte devices transducing novel vectors (Specific Aim #2) to evaluate the efficiency of the gene transfer and the expression of therapeutic genes in infected cells in vivo. The human hematopoietic cells will be recovered from various organs in the mouse, eg., the spleen or lymph nodes for the evaluation of the gene transfer. In another approach we will use immunocompetent mice and rats to investigate (i) immune responses against the helper cells and vector particles and (ii) test whether retroviral vectors specific for neuronal cells can be delivered to the brain through Theracyte implantation bags (Specific Aim #3).

描述（由申请人提供）：在过去的十年中， Domburg博士的实验室一直集中在细胞类型特定的发展上 逆转录病毒载体，衍生自禽网状内皮症 病毒，脾脏坏死病毒，SNV和网状内膜病毒A菌株A， Rev-a。已经开发了细胞型逆转录病毒载体颗粒， 这使高效的基因转导向人的细胞 造血系统。 SNV和REV-A的基质（MA）蛋白质的修饰 启用了静态造血细胞的基因转导。使用SCID小鼠， 皮下肿瘤作为模型，我们的初步数据表明目标细胞 可以用SNV衍生的逆转录病毒在体内获得特定的基因递送 植入Thenacyte免疫分散装置的载体。我们将继续使用 当前的模型系统，以进一步评估（i）持续时间和效率 基因转移和（ii）建立选定的包装细胞线 选择并优化，以通过Theracyte有效地体内基因递送 植入袋（特定目标＃1）。将开发新的向量系统 可以使用Theracyte免疫共溶于使用的研究来扩展我们的研究 （i）Hu-PBL-SCID小鼠和人类造血细胞作为靶标和（II）小鼠 基因输送到神经元细胞的模型。辅助细胞将植入 Theracyte设备传递新型矢量（特定目的＃2）以评估 基因转移的效率和治疗基因在中的表达 体内感染细胞。人类造血细胞将从 小鼠中的各种器官，例如脾或淋巴结进行评估 基因转移。在另一种方法中，我们将使用免疫能力的小鼠， 大鼠研究（i）针对辅助细胞和载体的免疫反应 颗粒和（ii）测试逆转录病毒载体是否针对神经元细胞 可以通过Theacyte植入袋将其传递到大脑（特定目的 ＃3）。