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，以评估用EFS-ADA慢病毒载体（LV）转导的自体骨髓CD34+细胞在非清髓性条件下接受布硫凡化疗后移植的安全性和有效性。腺苷脱氨酶（ADA）缺陷严重联合免疫缺陷（SCID）已使用？逆转录病毒(?-RV)介导的基因转移到骨髓CD34+造血干细胞（HSC）的最新临床试验。通过血液细胞中ADA酶活性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。然而，淋巴细胞恢复的速度相对较慢，达到的淋巴细胞的绝对水平往往低于正常水平，并且大多数受试者没有有效的B细胞重建和免疫球蛋白的产生。基因转移到人HSC的效率-RV是中度的，部分原因是这些载体在临床规模上的滴度相对较低。- rv有可能通过插入细胞原癌基因附近的强增强子元件导致插入性癌发生。慢病毒载体（LV）可以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HSC中，从而保持干细胞的植入能力。该试验将验证以下假设：与之前使用？-逆转录病毒载体(？

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.