EFS-ADA Lentiviral Vector Transduction of Bone Marrow CD34+ Cells for ADA-SCID

EFS-ADA 慢病毒载体转导骨髓 CD34+ 细胞用于 ADA-SCID

基本信息

批准号：
8713915
负责人：
Donald B Kohn
金额：
$ 68.69万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8713915
关键词：
Accounting Adenine Nucleotides Allogeneic Bone Marrow Transplantation Antibodies Antigens Autologous Autologous Bone Marrow Transplantation B-Lymphocytes Bioinformatics Blood Cells Bone Marrow Bone Marrow Cells Bone Marrow Stem Cell Bone Marrow Transplantation Busulfan CD14 gene CD19 gene CD3 Antigens CD34 gene Carbohydrates Cell Therapy Cells Cessation of life Child Clinical Clinical Research Clinical Trials Complementary DNA Complication Control Groups DNA Development Diagnosis Disease Disease-Free Survival Drug Metabolic Detoxication Effectiveness Engraftment Enhancers Enrollment Enzymes Erythrocytes Event Frequencies Gene Expression Gene Transfer Genes Genetic Enhancer Element Hematopoietic stem cells Human Immune Immune system Immunoglobulin A Immunoglobulin G Immunoglobulin M Immunoglobulins Immunologic Deficiency Syndromes Infant Institution Lead Lentivirus Vector Leukocytes Longitudinal Studies Lymphocyte Lymphocyte Count Marrow Measures Mediating Mitogens Myelogenous Myeloid Cells Patients Pediatric Hospitals Performance Peripheral Blood Lymphocyte Peripheral Blood Mononuclear Cell Phase Principal Investigator Procedures Production Proteins Proto-Oncogenes Recovery Retroviral Vector Risk SCID Mice Safety Severe Adverse Event Siblings Site Stem cells T-Lymphocyte Testing Tetanus Toxoid Therapeutic Time Transplantation United States National Institutes of Health adenosine deaminase alanine aminopeptidase cellular transduction chemotherapy clinical research site cohort conditioning enzyme activity enzyme replacement therapy follow-up gene correction gene therapy granulocyte immune function improved in vivo indexing inorganic phosphate preclinical study programs promoter reconstitution response transduction efficiency tumorigenesis vector

项目摘要

DESCRIPTION (provided by applicant): We propose a Phase I/II clinical trial to assess the safety and efficacy of transplanting autologous bone marrow CD34+ cells transduced with the EFS-ADA lentiviral vector (LV) following non-myeloablative conditioning with busulfan chemotherapy. Adenosine deaminase (ADA)-deficient severe combined immune deficiency (SCID) has been treated using ?-retroviral (?-RV)-mediated gene transfer to bone marrow CD34+ hematopioetic stem cells (HSC) in recent clinical trials. Stable engraftment of gene-corrected HSC has been achieved with in vivo expression of ADA enzyme activity in blood cells and substantial immune reconstitution in the majority of subjects. However, the pace of lymphocyte recovery is relatively slow and the absolute levels of lymphocytes reached are often sub-normal, and the majority of subjects do not have effective B cell reconstitution and immunoglobulin production. The efficiency of gene transfer to human HSC using??-RV is moderate, limited in part by the relatively low titers of these vectors when made at clinical scale Additionally???-RVs have the potential for causing insertional oncogenesis by insertion of their strong enhancer elements adjacent to cellular proto-oncogenes. Lentiviral vectors (LV) can be configured to have minimal enhancer activity in the transcriptional units and may be safer than ?-RV. Also, LV may transfer genes more efficiently to human HSC in a shorter time of culture preserving stem cell engraftment capacity. This trial will test the hypothesis that: the EFS-ADA lentiviral vector will safely lead to more engrafted, transduced HSC with better immune reconstitution compared to a historical control group in prior trials using ?-retroviral vectors (? RV). This 5-year study will enroll 10 ADA-deficient SCID patients through two sites (UCLA and NIH). Three to four patients will be enrolled annually during a 3-year accrual period and each patient will be followed for two years. There will be a separate study for long-term follow-up for these patients for years 3-15. If successful, this approach may lead to an alternative therapeutic approach to patients with ADA-deficient SCID, and other primary immune deficiencies and blood cell diseases.

描述（由申请人提供）：我们提出了一项I/II期临床试验，以评估移植自动溶液性慢病毒载体（LV）转导的移植自体骨髓CD34+细胞的安全性和功效。在最近的临床试验中，使用？ - 逆转录病毒（？-RV）介导的基因转移到骨髓CD34+血小质量干细胞（HSC）的基因转移了腺苷脱氨酶（ADA）缺乏严重的严重合并免疫缺陷（SCID）。通过体内ADA酶活性在血细胞中的体内表达和大多数受试者的实质性免疫重建，已经实现了基因校正的HSC的稳定植入。但是，淋巴细胞恢复的速度相对较慢，并且达到的淋巴细胞的绝对水平通常是亚正常的，并且大多数受试者没有有效的B细胞重构和免疫球蛋白产生。使用?? - RV转移到人HSC的基因效率是中等的，部分受这些载体的相对较低滴度的限制，当时在临床规模上进行了相对较低的滴度。可以将慢病毒载体（LV）配置为在转录单元中具有最小的增强剂活性，并且可能比？-RV更安全。同样，在培养时间较短的时间内，LV可以更有效地将基因转移到人HSC中，从而保留干细胞的植入能力。该试验将检验以下假设：与先前使用？逆转录病毒载体相比，与先前试验中的历史对照组相比，EFS-ADA慢病毒载体将安全地导致更植入，转导的HSC，并具有更好的免疫重构（免疫重建）（？？ RV）。这项为期5年的研究将通过两个部位（UCLA和NIH）招募10名ADA缺陷型SCID患者。在3年的应计期间，每年将参加三到四名患者，每位患者将持续两年。这些患者将有一项单独的研究3 - 15年。如果成功，这种方法可能会导致患有ADA缺乏SCID的患者以及其他原发性免疫缺陷和血细胞疾病的替代治疗方法。