Lentiviral Gene Therapy for Sickle Cell Disease and Immunodeficiency Disorders

描述(由申请人提供)： 该计划项目的总体目标是开发慢病毒载体，用于镰状细胞病(SCD)、Wiscott-Aldrich综合征(Was)和X连锁严重联合免疫缺陷(SCIDXI)患者。中心的统一假设是，含有绝缘体元件和适当的内部启动子的自失活慢病毒载体将安全有效地治疗这些血液和免疫细胞疾病。我们的总体方法建立在上一次筹资期间取得的进展的基础上，该进展导致了用于血红蛋白疾病的新型SEN HIV载体和SCID-XL具有明显较低的无意激活细胞原癌基因的倾向。我们最近还开发了一个稳定的慢病毒产生系统，这将极大地促进所有三种疾病的临床媒介生产。在项目1中，我们将生成和测试SCD的改良载体，并开发新的造血干细胞扩增和转导方法。在项目2中，将在临床前模型中测试AS的慢病毒载体的有效性和安全性，随后将在AS基因治疗的临床试验中进行测试。在项目3中，SCID-XL慢病毒载体现有稳定的生产细胞系将用于支持SCID-XL的两项临床试验；一项针对新诊断的患者，另一项针对先前治疗失败的大龄儿童。这些核心提供了这3个项目所需的基础设施要素。行政核心A将为政治行动办公室的活动提供一般行政支助。干细胞核心B将在临床前实验和临床试验中提供处理和转导造血干细胞的手段。载体Core C将为所有3个项目提供稳定的慢病毒生产者克隆，并为临床试验中使用的载体的生产和认证提供方法。免疫学核心D将提供临床研究所需的标准化免疫重建分析，并协助方案患者的招募和护理。这些项目和核心具有高度的协同性和广泛的互补性。总体而言，我们预计这项提案中的工作将导致高度影响的临床结果，这些结果将确定慢病毒载体在治疗这些疾病中的作用，并将为使用慢病毒载体进行人类干细胞基因治疗提供开创性的信息。

DESCRIPTION (provided by applicant): The overall goal of this Program Project is to develop lentiviral vectors for use in patients with sickle cell disease (SCD), Wiscott-Aldrich Syndrome (WAS), and X-linked severe combined immunodeficiency (SCIDXI). The central unifying hypothesis is that self-inactivating (SIN) lentiviral vectors containing insulator elements and appropriate intemal promoters will be both safe and effective for the treatment of these blood and immune cell disorders. Our general approach builds upon progress during the last funding period that has led to novel SEN HIV vectors for hemoglobinopathies and SCID-Xl that have a markedly lower propensity for inadvertent activation of cellular proto-oncogenes. We have also recently developed a stable lentiviral producer system that will greatly facilitate clinical vector production for all 3 disorders. In Project 1, we will generate and test improved vectors for SCD and develop new methods for expansion and transduction of hematopoietic stem cells. In Project 2, lentiviral vectors for WAS will be tested in preclinical models for efficacy and safety and later in a clinical trial of WAS gene therapy. In Project 3, an existing stable producer cell line for a SCID-Xl lentiviral vector will be used to support two clinical trials for SCID-Xl; one for newly diagnosed patients and a second trial for older children that have failed prior therapy. The Cores provide the infrastructural elements that are necessary for these 3 projects. Administrative Core A will provide general administrative support for the POl activities. Stem Cell Core B will provide the means for processing and transducing HSCs, both in preclinical experiments and in the clinical trials. Vector Core C will derive stable lentiviral producer clones for all 3 projects and provide methods for the production and certification of vectors used in the clinical trials. Immunology Core D will provide standardized immunologic reconstitution assays required for the clinical studies and assist in the recruitment and care of protocol patients. The Projects and Cores are highly synergistic and have extensive complementary interactions. Overall, we expect that the work in this proposal will lead to high impact clinical results that will define the role of lentiviral vectors for the treatment of these diseases, and that will provide pioneering information regarding the use of lentiviral vectors for human stem cell gene therapy.