Artemis (DCLRE1C ) Deficient Severe Combined Immunodeficiency
Conditions
Keywords
Artemis deficient Severe Combined Immunodeficiency, Severe Combined Immunodeficiency, Gene therapy, Allogeneic hematopoietic stem cells transplantation
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.
Interventions
GENETICARTEGENE drug product
Each patient will receive a single intravenous infusion of ARTEGENE drug product at D0.
Sponsors
Assistance Publique - Hôpitaux de Paris
URC-CIC Paris Descartes Necker Cochin
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 47 Months
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of transplant related mortality | Up to 100 days post treatment | — |
| Transgene copy number on peripheral blood mononuclear cells (PBMCs) | Up to 15 years post treatment | 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 |
| 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) |
| Adverse events | Up to 15 years post treatment | Frequency and severity of clinical AEs and changes in laboratory parameters |
| Transgene copy number in the transduced CD34+ cells in the drug substance | At Day 0 | by qPCR |
| 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 | — |
| Change in repertoire of T lymphocytes | 12, 24 months post treatment | via high-throughput sequencing of the TCR |
| Evaluation of the B lymphocyte compartment | 6 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| End of ongoing infection before the transplantation | Up to 15 years post treatment | — |
| Kinetics of immune reconstitution | Up to 15 years post treatment | Kinetics of immune reconstitution |
| Adverse event | Up to 15 years post treatment | Adverse event will be measured using CTCAE |
Countries
France
Contacts
STUDY_DIRECTORChantal Lagresle-Peyrou, MD
Imagine
CONTACTMarina CAVAZZANA, MD, PhD
CONTACTJinmi BAEK, Master
STUDY_DIRECTORAlessandra MAGNANI, MD, PhD
Department of Biotherapy,LTCG, Necker-Enfants Malades Hospital
Outcome results
None listed