Safety and Efficacy Study of Transplantation of Autologous CD34+ Cells Transduced With the G2ARTE Lentiviral Vector Expressing the DCLRE1C cDNA in Artemis (DCLRE1C) Deficient Severe Combined Immunodeficiency Patients (ARTEGENE)
- Conditions
- Artemis (DCLRE1C ) Deficient Severe Combined Immunodeficiency
- Interventions
- Genetic: ARTEGENE drug product
- Registration Number
- NCT05071222
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 5
- 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.
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description ARTEGENE drug product ARTEGENE drug product Autologous purified CD34+ cells transduced with a self-inactivated lentiviral vector, expressing the DCLRE1C gene (alias Artemis)
- Primary Outcome Measures
Name Time Method Transgene copy number in the transduced CD34+ cells in the drug substance At Day 0 by qPCR
Transgene copy number on sorted cell populations 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 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) 3 months post treatment Absence of any severe adverse events due to insertional mutagenesis Up to 15 years post treatment Change in Artemis mRNA levels 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 12, 24 months post treatment via high-throughput sequencing of the TCR
Incidence of transplant related mortality At 6 months post treatment Transgene copy number on peripheral blood mononuclear cells (PBMCs) Up to 15 years post treatment by qPCR
Adverse events Up to 15 years post treatment Frequency and severity of clinical AEs and changes in laboratory parameters
Change in total number of T cells 6, 12, 24 months post treatment by flow cytometry
Change in distribution of different subpopulations 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
Change in T lymphocyte in vitro proliferation in the presence of mitogens and antigens 6, 12, 24 months post treatment
- Secondary Outcome Measures
Name Time Method End of ongoing infection before the transplantation Up to 15 years post treatment Adverse event Up to 15 years post treatment Adverse event will be measured using CTCAE
Kinetics of immune reconstitution Up to 15 years post treatment Kinetics of immune reconstitution
Trial Locations
- Locations (1)
Department of Pediatric Immunology, Hematology and Rheumatology UIHR, Necker-Enfants Malades Hospital
🇫🇷Paris, France