Baboon envelope LVs efficiently transduced human adult, fetal, and progenitor T cells and corrected SCID-X1 T-cell deficiency

T cellsrepresent a valuable tool for treating cancers and infectious and inherited diseases; however, they are mainly short-lived in vivo. T-celltherapies would strongly benefit from gene transfer into long-lived persisting naive T cellsor T-cell progenitors. Here we demonstrate that baboonenvelope glycoprotein pseudotypedlentiviral vectors (BaEV-LVs) far outperformed other LV pseudotypesfor transduction of naive adult and fetal interleukin-7–stimulated T cells. Remarkably, BaEV-LVs efficiently transduced thymocytes and T-cell progenitorsgenerated by culture of CD34 + cells on Delta-like ligand 4 (Dll4). Upon NOD/SCIDγC −/− engraftment, high transduction levels (80%-90%) were maintained in all T-cellsubpopulations. Moreover, T-celllineage reconstitution was accelerated in NOD/SCIDγC −/− recipients after T-cell progenitorinjection compared with hematopoietic stem celltransplantation. Furthermore, γC-encoding BaEV-LVs very efficiently transduced Dll4-generated T-cellprecursors from a patient with X-linked severe combined immunodeficiency(SCID-X1), which fully rescued T-celldevelopment in vitro. These results indicate that BaEV-LVs are valuable tools for the genetic modification of naive T cells, which are important targets for gene therapy. Moreover, they allowed for the generation of gene-corrected T-cell progenitorsthat rescued SCID-X1 T-celldevelopment in vitro. Ultimately, the coinjection of LV-corrected T-cell progenitorsand hematopoietic stem cellsmight accelerate T-cellreconstitution in immunodeficient patients.