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)

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05071222

Collaborator

(none)

Enrollment

Location

Arm

216

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Artemis (DCLRE1C ) Deficient Severe Combined Immunodeficiency	Genetic: ARTEGENE drug product	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

5 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Oct 1, 2021

Anticipated Primary Completion Date :

Oct 1, 2039

Anticipated Study Completion Date :

Oct 1, 2039

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: ARTEGENE drug product

Autologous purified CD34+ cells transduced with a self-inactivated lentiviral vector, expressing the DCLRE1C gene (alias Artemis)

Genetic: ARTEGENE drug product

Each patient will receive a single intravenous infusion of ARTEGENE drug product at D0.

Outcome Measures

Primary Outcome Measures

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) [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)
Evaluation of the B lymphocyte compartment [At 12 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)
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)

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 1 Year

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient less than one year
SCID patients with confirmed biallelic mutations in the Artemis (DCLRE1C) gene
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
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 nivestim or busulfan
Unable to tolerate general anesthesia and/or marrow harvest or peripheral blood stem cell collection (apheresis) or insertion of central venous catheter.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Pediatric Immunology, Hematology and Rheumatology UIHR, Necker-Enfants Malades Hospital	Paris		France	75015

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Investigators

Study Director: Alessandra MAGNANI, MD, PhD, Department of Biotherapy,LTCG, Necker-Enfants Malades Hospital
Study Director: Chantal Lagresle-Peyrou, MD, IMAGINE