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: 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
• 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

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)：我们建议进行一项I/II期临床试验，以评估在非清髓性条件下接受白花丹化疗后，以EFS-ADA慢病毒载体(LV)转导的自体骨髓CD34+细胞移植的安全性和有效性。在最近的临床试验中，用逆转录病毒(？-RV)介导的基因转移骨髓CD34+造血干细胞(HSC)治疗了腺苷脱氨酶(ADA)缺乏的严重联合免疫缺陷(SCID)。基因修饰的HSC已经实现了稳定的植入，体内表达了血细胞中的ADA酶活性，并在大多数受试者中进行了实质性的免疫重建。然而，淋巴细胞恢复的速度相对较慢，达到的淋巴细胞绝对水平往往低于正常水平，大多数受试者没有有效的B细胞重建和免疫球蛋白产生。利用？？-RV将基因转移到人HSC的效率是中等的，部分原因是这些载体在临床规模上的滴度相对较低。另外，？？-RV有可能通过将其强大的增强子元件插入到细胞原癌基因附近而导致插入癌发生。慢病毒载体(LV)可以被配置为在转录单位具有最小的增强子活性，并且可能比？-RV更安全。此外，LV可以在较短的培养时间内更有效地将基因转移到人HSC，保持干细胞植入能力。这项试验将检验这样的假设：与先前使用逆转录病毒载体(？)的历史对照组相比，EFS-ADA慢病毒载体将安全地导致更多的移植、转导的HSC具有更好的免疫重建。 房车)。这项为期5年的研究将通过两个地点(加州大学洛杉矶分校和美国国立卫生研究院)招募10名ADA缺乏的SCID患者。在三年的累计期内，每年将有三到四名患者入选，每个患者将接受两年的跟踪调查。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，这种方法可能会导致另一种治疗方法，用于治疗ADA缺乏的SCID患者以及其他原发免疫缺陷和血细胞疾病。