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

• Published in: Blood advances 2019-02, Vol.3 (3), p.461-475
• Main Authors: Bernadin, Ornellie, Amirache, Fouzia, Girard-Gagnepain, Anais, Moirangthem, Ranjita Devi, Lévy, Camille, Ma, Kuiying, Costa, Caroline, Nègre, Didier, Reimann, Christian, Fenard, David, Cieslak, Agata, Asnafi, Vahid, Sadek, Hanem, Mhaidly, Rana, Cavazzana, Marina, Lagresle-Peyrou, Chantal, Cosset, François-Loïc, André, Isabelle, Verhoeyen, Els
• Format: Article
• Language: English
• Subjects: Animals; Cellular Biology; Gene Therapy; Lentivirus - genetics; Life Sciences; Mice; Mice, Inbred NOD; Mice, SCID; Papio; Stem Cells - metabolism
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2018027508

T cells represent a valuable tool for treating cancers and infectious and inherited diseases; however, they are mainly short-lived in vivo. T-cell therapies would strongly benefit from gene transfer into long-lived persisting naive T cells or T-cell progenitors. Here we demonstrate that baboon envelope glycoprotein pseudotyped lentiviral vectors (BaEV-LVs) far outperformed other LV pseudotypes for transduction of naive adult and fetal interleukin-7–stimulated T cells. Remarkably, BaEV-LVs efficiently transduced thymocytes and T-cell progenitors generated 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-cell subpopulations. Moreover, T-cell lineage reconstitution was accelerated in NOD/SCIDγC−/− recipients after T-cell progenitor injection compared with hematopoietic stem cell transplantation. Furthermore, γC-encoding BaEV-LVs very efficiently transduced Dll4-generated T-cell precursors from a patient with X-linked severe combined immunodeficiency (SCID-X1), which fully rescued T-cell development 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 progenitors that rescued SCID-X1 T-cell development in vitro. Ultimately, the coinjection of LV-corrected T-cell progenitors and hematopoietic stem cells might accelerate T-cell reconstitution in immunodeficient patients. [Display omitted]