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

• 批准号: 9116606
• 负责人: Donald B Kohn
• 金额: $ 59.27万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116606
• 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; Mitogens; Myelogenous; Myeloid Cells; Patients; Pediatric Hospitals; Performance; Peripheral Blood Lymphocyte; Peripheral Blood Mononuclear Cell; Phase; 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; Transactivation; 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; integration site; preclinical study; promoter; reconstitution; response; retroviral-mediated; transduction efficiency; tumorigenesis; vector

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 γ-retroviral (γ-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 γ-RV is moderate, limited in part by the relatively low titers of these vectors when made at clinical scale. Additionally, γ-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 γ-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 γ-retroviral vectors (γ-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）：我们提出一项 I/II 期临床试验，以评估在白消安化疗非清髓性预处理后移植用 EFS-ADA 慢病毒载体 (LV) 转导的自体骨髓 CD34+ 细胞的安全性和有效性。在最近的临床试验中，腺苷脱氨酶 (ADA) 缺陷的严重联合免疫缺陷 (SCID) 已通过 γ-逆转录病毒 (γ-RV) 介导的基因转移至骨髓 CD34+ 造血干细胞 (HSC) 进行治疗。通过血细胞中 ADA 酶活性的体内表达以及大多数受试者的大量免疫重建，已经实现了基因校正 HSC 的稳定植入。然而，淋巴细胞恢复的速度相对缓慢，并且淋巴细胞达到的绝对水平常常低于正常水平，并且大多数受试者没有有效的B细胞重建和免疫球蛋白产生。使用 γ-RV 将基因转移至人类 HSC 的效率中等，部分受到这些载体在临床规模生产时滴度相对较低的限制。此外，γ-RV 有可能通过将其强增强子元件插入细胞原癌基因附近而引起插入性肿瘤发生。慢病毒载体 (LV) 可配置为在转录单元中具有最小的增强子活性，并且可能比 γ-RV 更安全。此外，LV 可以在更短的培养时间内更有效地将基因转移到人类 HSC，从而保留干细胞的植入能力。该试验将检验以下假设：与之前使用 γ-逆转录病毒载体 (γ-RV) 的试验中的历史对照组相比，EFS-ADA 慢病毒载体将安全地产生更多移植、转导的 HSC，并具有更好的免疫重建。这项为期 5 年的研究将通过两个中心（UCLA 和 NIH）招募 10 名 ADA 缺陷 SCID 患者。在 3 年的累积期内，每年将招募 3 至 4 名患者，每位患者将接受两年的随访。将有一项单独的研究对这些患者进行 3-15 年的长期随访。如果成功，这种方法可能会为 ADA 缺陷 SCID 以及其他原发性免疫缺陷和血细胞疾病患者提供替代治疗方法。