Lentiviral Gene Therapy for Sickle Cell Disease And Immunodeficiency Disorders

项目概要-总体 该PPG专注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 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CD 34 + HSC，将在基于白消安的预处理后给予，并在 一系列临床前研究和人体临床试验。在项目1中，韦斯博士和他的同事将验证一个 一种新的高滴度慢病毒载体，用于BCL 11 A shRNA的红系特异性表达，并在临床中对其进行测试。 SCD基因治疗的临床试验与此同时，将开发基因组编辑方法来解除胎儿基因组的抑制。 在成人红细胞中检测血红蛋白（HbF），并在原代人CD 34 + HSC中检测。 在项目2中，博士。 罗林斯和他的同事将进行多中心试验，以评估安全性，可行性和有效性， WAS患者中的慢病毒基因转移。第二个目标将是开发有效的方法来利用基因组 编辑以通过靶向安全港基因座或通过校正内源WAS等位基因来校正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，沿着亚消融白消安预处理，治疗新诊断的婴儿和较大的儿童 关于XSCID这些研究将完成两项开放的XSCID基因治疗试验的招募，预计 从而将这种方法商业化。核心A将提供基本的行政支助， 各项目和中心之间的协调。核心B将为发展提供科学专门知识 以及为所有三个项目生产病毒载体。核心C将为所有慢病毒提供GMP生产 载体用于所有计划的临床试验，并提供GMP细胞加工以产生转导的CD 34 + HSC 参加圣犹大大学赞助的基因治疗试验总之，P01汇集了必要的专业知识， 在多中心联盟的背景下，充分开发针对这些选定疾病的基因疗法， 在这项工作所需的所有方面都具有多样和多学科的专门知识。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的方法， 系统，并提供了新的和高影响力的科学数据，将广泛地告知人类慢病毒/HSC基因 疗法

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.