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) (ARTEGENE)

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

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 Overview

• Status: Recruiting
• Conditions: Artemis (DCLRE1C ) Deficient Severe Combined Immunodeficiency
• Intervention / Treatment: Genetic: ARTEGENE drug product

• Study Type: Interventional
• Enrollment (Estimated): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Marina CAVAZZANA, MD, PhD; Phone Number: +33 144495068; Email: m.cavazzana@aphp.fr
• Study Contact Backup: Name: Jinmi BAEK, Master; Phone Number: +33 1 42 19 28 49; Email: jinmi.baek@aphp.fr

Study Locations

• France
  • Paris, France, 75015
    • Recruiting
    • Department of Pediatric Immunology, Hematology and Rheumatology UIHR, Necker-Enfants Malades Hospital
    • Contact: Despina MOSHOUS, MD, PhD; Email: despina.moshous@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 4 months (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: 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

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2023
• Primary Completion (Estimated): July 19, 2041
• Study Completion (Estimated): July 19, 2041

Study Registration Dates

• First Submitted: August 27, 2021
• First Submitted That Met QC Criteria: September 27, 2021
• First Posted (Actual): October 8, 2021

Study Record Updates

• Last Update Posted (Actual): November 27, 2023
• Last Update Submitted That Met QC Criteria: November 24, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Severe Combined Immunodeficiency; Gene therapy; Artemis deficient Severe Combined Immunodeficiency; Allogeneic hematopoietic stem cells transplantation
• Additional Relevant MeSH Terms: Metabolic Diseases; Immune System Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Severe Combined Immunodeficiency
• Other Study ID Numbers: D20180302; 2019-003555-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No