A Phase 1/2 Open Label Non Randomized Study, Multicentric, Single Arm Evaluating the Safety and Efficacy of Gene Therapy of the Severe Combined Immunodeficiency (SCID) Caused by Mutations in the Human DCLRE1C Gene (Artemis) by Transplantation of a Single Dose of Autologous CD34+ Cells Transduced ex Vivo With the G2ARTE Lentiviral Vector Expressing the DCLRE1C cDNA
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 5
- 试验地点
- 2
- 主要终点
- Transgene copy number on sorted cell populations
研究概览
简要总结
The purpose of this study is to evaluate the Safety and Efficacy of Gene Therapy of the severe combined immunodeficiency (SCID) caused by mutations in the human DCLRE1C gene (Artemis) by transplantation of a single dose of autologous CD34+ cells transduced ex vivo with the G2ARTE lentiviral vector expressing the DCLRE1C cDNA.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 47 Months（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient to 47 months
- •SCID patients with confirmed biallelic mutations in the Artemis (DCLRE1C) gene even in the case of leaky forms characterised by a residual activity
- •Absence of an HLA genoidentical donor or without rapidly available HLA-compatible unrelated donor (within six weeks of diagnosis)
- •The patient can be treated by gene therapy without delay in case of active life threatening infections compromising the short-term prognosis and for which the delay in finding a phenoidentical donor is incompatible with the patient's condition of health. Active life threatening infections are defined as: viral respiratory infection, CMV infection, adenovirus infection, disseminated BCGitis or other infections grade ≥ 4 according to CTCAE scale
- •Beneficiary of a social security scheme
- •Parental, guardian's patient signed informed consent.
- •Exclusion Criteria
- •Unwillingness to return for follow-up during the first 2 years study and the long term follow-up
- •HIV-1 or 2 or HTLV1 infections
- •Hypersensitivity to G-CSF, busulfan or Fludarabine
- •Unable to tolerate general anesthesia and/or marrow harvest or peripheral blood stem cell collection (apheresis) or insertion of central venous catheter.
排除标准
- 未提供
结局指标
主要结局
Transgene copy number on sorted cell populations
时间窗: Up to 15 years post treatment
Determined on sorted cell populations CD15+,CD14+, CD19+, CD56+ and CD3+ T lymphocytes by qPCR
Evaluation of the B lymphocyte compartment
时间窗: At 24 months post treatment
analysis of the circulating B cell subpopulations by flow cytometry: total CD19+ cells, naive (CD19+IgD+CD27-), switched memory (CD19+IgD-CD27+), marginal zone (CD19+IgD+CD27+), transitional (CD19+IgD+CD27-CD24highCD38+), 21low (CD19+CD38-CD21low). Immunoglobulin levels (IgG, A, M and E) and specific antibody production after immunization (if applicable)
Detection of replication-competent lentivirus (RCL)
时间窗: 3 months post treatment
Absence of any severe adverse events due to insertional mutagenesis
时间窗: Up to 15 years post treatment
Change in Artemis mRNA levels
时间窗: At Day 0, 12 months and 24 months post treatment
by RT-qPCR performed on the transduced CD34+ cells in the drug substance and on peripheral blood mononuclear cells (PBMC)
Change in repertoire of T lymphocytes
时间窗: 12, 24 months post treatment
via high-throughput sequencing of the TCR
Incidence of transplant related mortality
时间窗: At 6 months post treatment
Transgene copy number on peripheral blood mononuclear cells (PBMCs)
时间窗: Up to 15 years post treatment
by qPCR
Adverse events
时间窗: Up to 15 years post treatment
Frequency and severity of clinical AEs and changes in laboratory parameters
Change in total number of T cells
时间窗: 6, 12, 24 months post treatment
by flow cytometry
Change in distribution of different subpopulations
时间窗: 6, 12, 24 months post treatment
by flow cytometry, according to the WBC count: Naïve and activated/memory CD4+ and CD8+ T cells will be evaluated using CCR7/CD45RA/CD45RO markers. Early thymic emigrants will be monitored by detecting CD31+CD45RA+CD4+ T lymphocytes; Stem cell-like memory CD8+ and CD4+ T cells will be quantified by counting CCR7+CD45RA+CD8+ T cells. Evaluation of the distribution of TCRαβ and TCRγδ T cells
Transgene copy number in the transduced CD34+ cells in the drug substance
时间窗: At Day 0
by qPCR
Change in T lymphocyte in vitro proliferation in the presence of mitogens and antigens
时间窗: 6, 12, 24 months post treatment
次要结局
- End of ongoing infection before the transplantation(Up to 15 years post treatment)
- Adverse event(Up to 15 years post treatment)
- Kinetics of immune reconstitution(Up to 15 years post treatment)