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)

Phase 2RecruitingNCT05071222

Assistance Publique - Hôpitaux de Paris5 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Artemis (DCLRE1C ) Deficient Severe Combined Immunodeficiency

Interventions

ARTEGENE drug productGENETIC

Eligibility

Sex: ALLMax age: 47 Months

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Incidence of transplant related mortality

Time frame: Up to 100 days post treatment

Incidence of transplant related mortality

Time frame: At 6 months post treatment

Transgene copy number on peripheral blood mononuclear cells (PBMCs)

by qPCR

Time frame: 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

Time frame: Up to 15 years post treatment

Detection of replication-competent lentivirus (RCL)

Time frame: 3 months post treatment

Absence of any severe adverse events due to insertional mutagenesis

Time frame: 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)

Time frame: At Day 0, 12 months and 24 months post treatment

Adverse events

Frequency and severity of clinical AEs and changes in laboratory parameters

Time frame: Up to 15 years post treatment

Transgene copy number in the transduced CD34+ cells in the drug substance

by qPCR

Time frame: At Day 0

Change in total number of T cells

by flow cytometry

Time frame: 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

Time frame: 6, 12, 24 months post treatment

Change in T lymphocyte in vitro proliferation in the presence of mitogens and antigens

Time frame: 6, 12, 24 months post treatment

Change in repertoire of T lymphocytes

via high-throughput sequencing of the TCR

Time frame: 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)

Time frame: 6 months post treatment

Evaluation of the B lymphocyte compartment

Time frame: At 12 months post treatment

Evaluation of the B lymphocyte compartment

Time frame: At 24 months post treatment

Secondary Outcomes

End of ongoing infection before the transplantation

Time frame: Up to 15 years post treatment

Kinetics of immune reconstitution

Time frame: Up to 15 years post treatment

Adverse event

Adverse event will be measured using CTCAE

Time frame: Up to 15 years post treatment

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)

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts