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)

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Artemis (DCLRE1C ) Deficient Severe Combined Immunodeficiency

Intervention / Treatment
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* Genetic: ARTEGENE drug product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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.

Ages Eligible for Study
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Maximum Age: 47 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARTEGENE drug product<br>Autologous purified CD34+ cells transduced with a self-inactivated lentiviral vector, expressing the DCLRE1C gene (alias Artemis) | Genetic: ARTEGENE drug product<br>* Each patient will receive a single intravenous infusion of ARTEGENE drug product at D0.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of transplant related mortality |  | Up to 100 days post treatment | 
| Incidence of transplant related mortality |  | At 6 months post treatment | 
| Transgene copy number on peripheral blood mononuclear cells (PBMCs) | by qPCR | Up to 15 years post treatment | 
| Transgene copy number on sorted cell populations | Determined on sorted cell populations CD15+,CD14+, CD19+, CD56+ and CD3+ T lymphocytes by qPCR | Up to 15 years post treatment | 
| 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 | by RT-qPCR performed on the transduced CD34+ cells in the drug substance and on peripheral blood mononuclear cells (PBMC) | At Day 0, 12 months and 24 months post treatment | 
| Adverse events | Frequency and severity of clinical AEs and changes in laboratory parameters | Up to 15 years post treatment | 
| Transgene copy number in the transduced CD34+ cells in the drug substance | by qPCR | At Day 0 | 
| Change in total number of T cells | by flow cytometry | 6, 12, 24 months post treatment | 
| Change in distribution of different subpopulations | 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 | 6, 12, 24 months post treatment | 
| Change in T lymphocyte in vitro proliferation in the presence of mitogens and antigens |  | 6, 12, 24 months post treatment | 
| Change in repertoire of T lymphocytes | via high-throughput sequencing of the TCR | 12, 24 months post treatment | 
| Evaluation of the B lymphocyte compartment | 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) | 6 months post treatment | 
| Evaluation of the B lymphocyte compartment | 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) | At 12 months post treatment | 
| Evaluation of the B lymphocyte compartment | 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) | At 24 months post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| End of ongoing infection before the transplantation |  | Up to 15 years post treatment | 
| Kinetics of immune reconstitution | Kinetics of immune reconstitution | Up to 15 years post treatment | 
| Adverse event | Adverse event will be measured using CTCAE | Up to 15 years post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Artemis deficient Severe Combined Immunodeficiency, Severe Combined Immunodeficiency, Gene therapy, Allogeneic hematopoietic stem cells transplantation