CONDITIONAL ACTIVATION OF MPL AS A GENE THERAPY STRATEGY

有条件激活 MPL 作为基因治疗策略

• 批准号: 6721119
• 负责人: ROBERT E RICHARD
• 金额: $ 15.23万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6721119
• 关键词: CD34 molecule; NOD mouse; Retroviridae; SCID mouse; bone marrow; chimeric proteins; clinical research; clinical trials; dimer; disease /disorder model; gene therapy; genetic manipulation; growth factor receptors; growth media; hematopoietic stem cells; hematopoietic tissue transplantation; human subject; human therapy evaluation; hydroxyurea; patient oriented research; sample collection; sickle cell anemia; stem cell transplantation; thrombopoietic factor; transfection /expression vector; xenotransplantation

DESCRIPTION (provided by applicant): The goal of this proposal is to develop methods by which genetically modified hematopoietic cells can be selectively expanded and in so doing treat patients with sickle cell anemia. The investigators have demonstrated that chemical inducers of dimerization (CIDs) can selectively direct proliferation of transduced cells that express a fusion protein containing a CID binding domain linked to the intracellular portion of the thrombopoietin receptor, mpl. Their recent studies have shown that CID-mediated activation of the mpl fusion protein can direct expansion of genetically modified primary hematopoietic cells in vitro and in vivo. Using a retroviral vector that incorporates both a therapeutic globin cassette as well as a gene encoding the mpl fusion protein, they aim to specifically expand genetically corrected blood cells in vivo, and in the process make gene therapy safer and more effective. It is their intention to develop methods that will lead to a clinical trial in which patients with hemoglobinopathies will have their peripheral blood stem cells collected, transduced with a therapeutic vector, reinfused, followed by selective expansion of the corrected blood cells. These studies will be accomplished with the aid of the unique resources of the recently instituted Gene and Cell Therapy Laboratory at the UW Medical Center (UWMC). Their aims are as follows: 1) Develop methods for mobilization and collection of hematopoietic stem cells from patients with sickle cell disease. 2) Test whether CIDs can be used to selectively expand bone marrow progenitor cells transduced with a vector that encodes a humanized fusion protein and a (beta-like globin. 3) Test in vivo selection of genetically modified hematopoietic cells in a xenogeneic transplant model. 4) Develop necessary procedures for cell collection and transduction prior to initiating a clinical gene therapy trial in the hemoglobinopathies. At the conclusion of the above listed specific aims they will have developed a unique clinical reagent that will be ready for gene therapy trials. These goals are attainable given the unique facilities that are now available at the UW GCRC.

描述（由申请人提供）：该提案的目的是开发 可以选择性地选择性地修饰造血细胞的方法 扩展，因此治疗患有镰状细胞贫血的患者。 这 研究人员表明，化学诱导剂（CID） 可以选择性地直接表达融合的转导细胞的增殖 含有与细胞内部分相关的CID结合域的蛋白质 血小板蛋白受体，Mpl。 他们最近的研究表明 CID介导的MPL融合蛋白的激活可以直接膨胀 基因修饰的原代造血细胞在体外和体内。 使用 逆转录病毒矢量，将既有治疗性球蛋白盒式都纳入 以及编码MPL融合蛋白的基因，它们的目的是专门 扩展体内遗传校正的血细胞，并在此过程中使基因 治疗更安全，更有效。 他们打算开发将导致临床试验的方法 哪些血红蛋白病患者将患有外周血管 收集的细胞，用治疗载体转导，重新填充，然后是 校正血细胞的选择性扩张。 这些研究将是 借助最近建立的独特资源完成 UW医疗中心（UWMC）的基因和细胞治疗实验室。 他们的目标 如下： 1）开发动员和收集造血干细胞的方法 来自患有镰状细胞疾病的患者。 2）测试CID是否可以使用 有选择地扩大用载体转导的骨髓祖细胞细胞 编码人性化的融合蛋白和一个（β样球蛋白。3）在体内测试 在异构化中选择转基因造血细胞 移植模型。 4）为收集细胞制定必要的程序和 在启动临床基因治疗试验之前转导 血红蛋白病。 在上述列出的特定目标时，他们将开发一个 独特的临床试剂将准备进行基因治疗试验。 这些 鉴于现在可以在 UW GCRC。