Lentiviral Gene Therapy and Genome Editing for X-linked Severe Combined Immunodeficiency

X连锁严重联合免疫缺陷病的慢病毒基因治疗和基因组编辑

基本信息

批准号：
10453807
负责人：
Stephen Gottschalk
金额：
$ 57.62万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453807
关键词：
Adverse event Amendment B-Lymphocytes Biological Assay Blood Bone Marrow Bone Marrow Cells Busulfan CD34 gene California Cancer Center Cell Count Cell physiology Cells Cellular Immunity Child Childhood Clinical Clinical Trials Clonality Cyclic GMP Data Data Analyses Data Set Database Management Systems Databases Defect Disease Engraftment Enrollment Epigenetic Process Flow Cytometry Follow-Up Studies Funding Gamma globulin Gene therapy trial Genes Goals Hematopoietic Hematopoietic stem cells Homologous Transplantation Human Humoral Immunities IL2RG gene Immune Immune system Immunity Immunologic Deficiency Syndromes Immunologics Immunophenotyping Industrialization Infant Institutional Review Boards Lead Lentivirus Vector Life Longterm Follow-up Mediating Modernization Molecular Mus Mutation Myelogenous Myeloid Cells Natural Killer Cells Newly Diagnosed Outcome Patients Pediatric Hospitals Performance Phase Procedures Production Protocols documentation Replacement Therapy Reporting Research Retroviral Vector Risk Safety Saint Jude Children&apos s Research Hospital Sampling San Francisco Severe Combined Immunodeficiency Siblings Sickle Cell Anemia Site Sorting - Cell Movement T cell reconstitution T memory cell T-Lymphocyte Technology Testing Time Transplantation United States National Institutes of Health Universities Work X-Linked Severe Combined Immunodeficiency base cellular transduction clinical center commercialization conditioning curative treatments gene therapy genome editing genotoxicity graft vs host disease human subject immune function immune reconstitution improved leukemia novel novel strategies novel therapeutics performance site peripheral blood phase 1 study progenitor reconstitution success transplantation therapy vector vector genome

项目摘要

PROJECT SUMMARY – PROJECT 3 The overall goal of this project is to determine if lentiviral gene therapy combined with subablative busulfan conditioning can be used to treat a broad spectrum of patients with severe combined immunodeficiency (XSCID). This catastrophic disease of childhood is caused by mutations in the IL2RG gene that lead to profound defects in T cell, NK cell, and B-cell mediated immunity. Allogeneic transplant is the standard therapy, but results in suboptimal outcomes in patients that lack matched sibling donors. While prior gene therapy trials with gamma- retroviral vectors showed clinical benefit, incomplete immune reconstitution and vector-related leukemia was seen in a significant number of cases. We propose a new approach using a safety-modified lentiviral vector and reduced intensity conditioning in order establish long-term correction via bone marrow engraftment of transduced hematopoietic stem cells. During the past funding period, we opened the first clinical lentiviral trials with subablative busulfan for XSCID and have obtained remarkable success in 12 cases treated thus far. The LVXSCID-OC trial at the NIH Clinical Center has enrolled eight XSCID patients who had waning immunity despite having undergone a prior allogeneic transplant. These cases have shown high levels of myeloid marking that are unprecedented in prior XSCID gene therapy trials and complete immune reconstitution in some cases. In particular, B cell function was restored in the first two cases leading to independence from gamma-globulin replacement therapy, which has not been obtained in prior gene therapy trials. We have also opened a newly diagnosed protocol (LVXSCID-ND) at St. Jude, UCSF, and Seattle and have treated four infants with transduced bone marrow cells following targeted subablative conditioning over the past seven months. Gene marking in blood and bone marrow myeloid cells has been very high and has been associated with rapid reconstitution of T and NK cell numbers and function. B cell marking levels have averaged 0.8 copies/cell and have been noted with preliminary evidence of endogenous gamma-globulin production in one case. Based on these results, we now seek support to complete both of these Phase I studies by validating more GMP-grade vector batches, completing enrollment on both protocols, and performing detailed, long term analyses of immune reconstitution, vector marking/clonality studies, and clinical safety in these cases. We anticipate that these studies will provide a new therapy for XSCID and leading to commercialization of this gene therapy approach so that this treatment can be made widely available.

项目摘要 - 项目3 该项目的总体目标是确定慢病毒基因疗法是否与下busulfan结合调节可用于治疗严重合并免疫缺陷（XSCID）的广泛患者。这种灾难性的童年疾病是由IL2RG基因突变引起的，导致了深远的缺陷在T细胞中，NK细胞和B细胞介导的免疫力。同种异体移植是标准疗法，但导致缺乏匹配同胞供体的患者的次优效果。而γ-先前的基因治疗试验逆转录病毒载体显示临床益处，不完整的免疫重建和与矢量相关的白血病为在大量案例中可见。我们提出了一种使用安全修饰的慢病毒载体的新方法，然后降低强度调节以确定通过翻译的骨髓植入长期校正造血干细胞。在过去的资金期间，我们与用于XSCID的亚电体busulfan，并在迄今为止的12例治疗病例中取得了显着的成功。这 NIH临床中心的LVXSCID-OC试验已招募了八名XSCID患者，这些患者的免疫力降低了经过了先前的同种异体移植。这些病例显示出高水平的髓样标记在先前的XSCID基因治疗试验中是前所未有的，在某些情况下是完全免疫重建的。在特别是，在前两种情况下，B细胞功能恢复了，导致独立于γ-球蛋白替代疗法，在先前的基因治疗试验中尚未获得。我们还开了一个新的在圣裘德，UCSF和西雅图诊断的方案（LVXSCID-ND），并用翻译的四名婴儿治疗了在过去的七个月中，靶向下底部调节后的骨髓细胞。基因标记在血液和骨髓髓样细胞一直很高，并且与快速重建有关 T和NK单元格数和功能。 B细胞标记水平平均为0.8份/单元格，并已注意到在一种情况下，内源性γ-球蛋白产生的初步证据。基于这些结果，我们现在寻求支持以验证更多的GMP级矢量批处理，以完成这两个I阶段研究，完成这两个方案的注册，并执行细节，长期分析免疫财产宪法，在这些情况下，向量标记/克隆性研究和临床安全。我们预计这些研究将提供用于XSCID的新疗法并导致这种基因疗法的商业化，以便这种治疗可以广泛使用。