Lentiviral Gene Therapy for Sickle Cell Disease And Immunodeficiency Disorders

镰状细胞病和免疫缺陷病的慢病毒基因治疗

• 批准号: 10207728
• 负责人: Mitchell J Weiss
• 金额: $ 272.85万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207728
• 关键词: Adult; Alleles; Autologous; Blood; Blood Tests; Bone Marrow Stem Cell; Busulfan; CD34 gene; Cell Line; Cells; Certification; Child; Clinical; Clinical Trials; Cyclic GMP; Data; Development; Disease; Dose; Elements; Enhancers; Enrollment; Erythrocytes; Erythroid; Fetal Hemoglobin; Follow-Up Studies; Funding; Gene Transfer; Gene therapy trial; Generations; Goals; HIV; Hematopoietic System; Hematopoietic stem cells; Human; Immune; Immune System Diseases; Immune system; Immunologic Deficiency Syndromes; Infant; Infrastructure; Lead; Lentivirus Vector; Longterm Follow-up; Methods; Multi-Institutional Clinical Trial; Multicenter Trials; Newly Diagnosed; Patients; Performance; Pre-Clinical Model; Prior Therapy; Procedures; Process; Production; Program Research Project Grants; Proto-Oncogenes; Resources; Role; Safety; Saint Jude Children' s Research Hospital; Scientific Advances and Accomplishments; Series; Sickle Cell Anemia; Site; Techniques; Testing; Therapeutic; Transplantation; Use Effectiveness; Viral Vector; Wiskott-Aldrich Syndrome; Work; X-Linked Severe Combined Immunodeficiency; base; blood treatment; clinically translatable; commercialization; conditioning; design; effective therapy; gene therapy; genome editing; improved; improved outcome; multidisciplinary; novel; novel strategies; novel therapeutic intervention; novel therapeutics; preclinical study; programs; repaired; safety and feasibility; small hairpin RNA; vector

PROJECT SUMMARY – OVERALL This PPG is focused on developing safe and effective gene therapy approaches to treat sickle cell disease (SCD), Wiskott-Aldrich syndrome (WAS), and x-linked severe combined immunodeficiency (XSCID). Our overall approach is based on using self-inactivating lentiviral vectors as well as genome editing approaches to correct autologous CD34+ HSCs, which will be administered after busulfan-based conditioning and tested in a series of pre-clinical studies and human clinical trials. In Project 1, Dr. Weiss and his colleagues will validate a novel high-titer lentiviral vector for erythroid-specific expression of BCL11A shRNA and test this in a clinical trial for SCD gene therapy. In parallel, genome editing approaches will be developed to de-repress fetal hemoglobin (HbF) in adult red blood cells and tested in primary human CD34+ HSCs.  In Project 2, Dr. Rawlings and his colleagues will perform multi-center trials to evaluate the safety, feasibility, and efficacy of lentiviral gene transfer in WAS patients. The second aim will be to develop efficient means to use genome editing to correct WAS either by targeting safe harbor loci or by correcting the endogenous WAS allele. In Project 3, Dr. Sorrentino and his colleagues will prove the effectiveness of using the first lentiviral vector for XSCID, along with subablative busulfan conditioning, to treat both newly diagnosed infants and older children with XSCID. These studies will complete enrollment on two open XSCID gene therapy trials and are expected to lead to commercialization of this approach. Core A will provide essential administrative support and coordination between the various projects and centers. Core B will provide scientific expertise for development and production of viral vectors for all three projects. Core C will provide GMP manufacturing for all lentiviral vectors used all planned clinical trials, and provide GMP cell processing to generate transduced CD34+ HSCs for the St. Jude-sponsored gene therapy trials. Altogether, this P01 brings together the necessary expertise to fully develop gene therapy for these selected disorders in the context of a multi-center consortium providing diverse and multidisciplinary expertise in all required aspects of this work. Realization of the aims of this PPG will provide new approaches for treating these severe monogenetic disorders of the hematopoietic and immune system and provide novel and high impact scientific data that will broadly inform human lentiviral/HSC gene therapy.

项目概要——总体 该 PPG 致力于开发安全有效的基因治疗方法来治疗镰状细胞病 (SCD)、Wiskott-Aldrich 综合征 (WAS) 和 x 连锁严重联合免疫缺陷 (XSCID)。我们的 总体方法基于使用自失活慢病毒载体以及基因组编辑方法 正确的自体 CD34+ HSC，将在基于白消安的调理后进行管理并在 系列临床前研究和人体临床试验。在项目 1 中，Weiss 博士和他的同事将验证 新型高滴度慢病毒载体，用于 BCL11A shRNA 的红细胞特异性表达，并在临床中进行测试 SCD 基因治疗试验。与此同时，将开发基因组编辑方法来消除胎儿的抑制 成人红细胞中的血红蛋白 (HbF) 并在原代人 CD34+ HSC 中进行了测试。  在项目 2 中，博士。 罗林斯和他的同事将进行多中心试验来评估其安全性、可行性和有效性 WAS 患者的慢病毒基因转移。第二个目标是开发利用基因组的有效方法 通过针对安全港基因座或通过纠正内源 WAS 等位基因进行编辑以纠正 WAS。在 项目 3，Sorrentino 博士和他的同事将证明使用第一个慢病毒载体的有效性 XSCID 与亚消融白消安调理一起治疗新诊断的婴儿和年龄较大的儿童 与 XSCID。这些研究将完成两项开放 XSCID 基因治疗试验的入组，预计 导致这种方法的商业化。核心 A 将提供必要的行政支持和 各个项目和中心之间的协调。核心B将为发展提供科学专业知识 以及为所有三个项目生产病毒载体。 Core C将为所有慢病毒提供GMP生产 载体使用了所有计划的临床试验，并提供 GMP 细胞处理以生成转导的 CD34+ HSC 用于圣裘德赞助的基因治疗试验。总而言之，这款 P01 汇集了必要的专业知识， 在多中心联盟的背景下，全面开发针对这些选定疾病的基因疗法，提供 这项工作所有所需方面的多样化和多学科专业知识。实现本 PPG 的目标 将为治疗这些严重的造血和免疫单基因疾病提供新方法 系统并提供新颖且具有高影响力的科学数据，为人类慢病毒/HSC 基因提供广泛信息 治疗。