OR16

Gene therapy for Artemis-SCID patients: preliminary results of the French ARTEGENE phase I/II clinical trial

J S Diana(1,2) B Bessot(1,3) D Moshous(4) M Castelle(4) E Magrin(1,2) M Chbihi(4) P Bastard(4) A Girardot(2) C Mollet(2) C Aussel(1,2) E Schwartz(1,2) N Sorel(1,3) O Neth(5) P Olbrich(6) I D'Alba(7) J Rivière(8) M Oualha(9) L Joseph(2) B Neven(4) J P de Villartay(10) A Galy(11) C Lagresle-Peyrou(1,3) M Cavazzana(1,2,3)

1:Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AssistancePublique-Hôpitaux de Paris, INSERM, Paris, France; 2:Department of Biotherapy, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, 75015 France; 3:UMR 1163, INSERM, Paris Descartes University Sorbonne Paris Cité, Imagine Institute, Paris 75015, France; 4:Department of Pediatric Immunology, Hematology, and Rheumatology, Necker-Enfants Malades University Hospital, APHP, F-75015 Paris, France; 5:Unit of Infectious Diseases, Rheumatology, and Immunology; Hospital Infantil Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla (IBiS), Spain; 6:Paediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocío, Seville, Spain; 7:Paediatric Haematology-Oncology, Maternal Infant Hospital "G. Salesi,", Ancona, Italy; 8:Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain; 9:Pediatric Intensive Care Unit Necker-Enfants Malades University Hospital, APHP, F-75015 Paris, France; 10:Laboratory of Genome Dynamics in the Immune System, UMR1163, INSERM, Paris Descartes University Sorbonne Paris Cité, Imagine Institute, Paris, 75015 France; 11:US35 INSERM, ART-TG, Corbeil-Essonnes, France

Genetic deficiency of the endonuclease DCLRE1C/Artemis, a key factor of the DNA repair machinery, causes Severe Combined Immunodeficiency (SCID) characterized by a complete lack of T and B cells. Allogeneic bone-marrow transplantation is the gold standard to cure the disease but the outcome is not satisfactory with partial haplo-identical donors.  In this context, autologous gene therapy (GT) for Artemis-SCID represents a good alternative. Recently, a GT phase I/II clinical trial (ARTEGENE -NCT05071222) was started at the Necker Hospital, Paris. The first patient (P1) included had a true SCID phenotype but maternal T cells requiring a corticosteroid treatment. During apheresis, we collected mobilized peripheral blood (mPB) and bone marrow (BM) cells for immunophenotyping. Our data demonstrated that the proportions of Hematopoietic Stem and Progenitor Cells (HSPCs) and CD34+CD19+ pro-B cells differs according to the cell source. We also collected P1-transduced HSPCs and after in vitro culture, these cells differentiated into pro-T cells and initiated T-cell rearrangements. In a xenotransplantation model, they colonized the thymus and differentiated until the CD3+TCRaB+ stage. At 6 months post-GT, P1 patients had a stable vector copy number of 1, similar to the one found in the drug product. The T and B cell reconstitution increased with time and reached normal values at 12 months post-transplant. Our data highlighted that ARTEGENE gene transfer strategy restore a functional T- and B-cell compartment in Artemis SCID patient. To date, three patients have been included in this trial and the follow-up is ongoing.