Restoration of T and B Cell Differentiation after RAG1 Gene Transfer in Human RAG1 Defective Hematopoietic Stem Cells.

Recombinase-activating gene (RAG)-deficient SCID patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. The two genes act as a required dimer to initiate gene recombination. Gene therapy is a valid treatment alternative for RAG-SCID patients who lack a suitable bone marrow donor, but developing such therapy for RAG1/2 has proven challenging. Using a clinically approved lentiviral vector with a codon-optimized gene, we report here preclinical studies using CD34+ cells from four RAG1-SCID patients. We used in vitro T cell developmental assays and in vivo assays in xenografted NSG mice. The RAG1-SCID patient CD34 cells transduced with the RAG1 vector and transplanted into NSG mice led to restored human B and T cell development. Together with favorable safety data on integration sites, these results substantiate an ongoing phase I/II clinical trial for RAG1-SCID.

DOI: 10.3390/biomedicines12071495, PMID: 39062069
Authors: Nataël Sorel, Francisco Díaz-Pascual, Boris Bessot, Hanem Sadek, Chloé Mollet, Myriam Chouteau, Marco Zahn, Irene Gil-Farina, Parisa Tajer, Marja van Eggermond, Dagmar Berghuis, Arjan C Lankester, Isabelle André, Richard Gabriel, Marina Cavazzana, Kasrin Pike-Overzet, Frank J T Staal, Chantal Lagresle-Peyrou