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

描述（由申请人提供）：我们提出了一项I/II期临床试验，以评估在白消安化疗的非清髓性预处理后移植EFS-ADA慢病毒载体（LV）转导的自体骨髓CD 34+细胞的安全性和有效性。腺苷脱氨酶（ADA）缺陷型严重联合免疫缺陷（SCID）已使用？逆转录病毒（？- RV）介导的基因转移至骨髓CD 34+造血干细胞（HSC）的研究进展。在大多数受试者中，基因校正的HSC的稳定植入已经通过血细胞中ADA酶活性的体内表达和实质性免疫重建实现。然而，淋巴细胞恢复的速度相对缓慢，达到的淋巴细胞绝对水平通常低于正常水平，大多数受试者没有有效的B细胞重建和免疫球蛋白产生。用？RV为中度，部分受限于临床规模制备时这些载体的滴度相对较低。RV具有通过在细胞原癌基因附近插入其强增强子元件而引起插入性肿瘤发生的潜力。慢病毒载体（LV）可以被配置为在转录单位中具有最小的增强子活性，并且可能比？RV。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中，从而保留干细胞植入能力。本试验将检验以下假设：与既往试验中使用？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HSC，并具有更好的免疫重建。逆转录病毒载体（？ RV）。这项为期5年的研究将通过两个研究中心（UCLA和NIH）招募10名ADA缺陷型SCID患者。在3年的招募期内，每年将入组3 - 4例患者，每例患者将接受2年随访。将对这些患者进行3-15年的单独长期随访研究。如果成功，这种方法可能会为ADA缺陷型SCID患者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。 公共卫生相关性：这项临床试验将寻求开发更好的治疗原发性免疫缺陷（PID）疾病的方法，使用慢病毒载体将正常基因转移到骨髓干细胞。它将提供关于这种细胞和基因联合治疗方法的安全性和有效性的首次人体信息，并将支持开发更好的PID和其他血细胞疾病治疗方法。

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. PUBLIC HEALTH RELEVANCE: This clinical trial will seek to develop better treatments for Primary Immune Deficiency (PID) disorders, using lentiviral vectors to transfer the normal gene to bone marrow stem cells. It will provide first-in-human information on the safety and effectiveness of this combined cell and gene therapy approach and would support the development of better treatments for PID and other blood cell diseases.