Efficacy of lentivirus-mediated gene therapy in an Omenn syndrome recombination-activating gene 2 mouse model is not hindered by inflammation and immune dysregulation - 06/09/18
Abstract |
Background |
Omenn syndrome (OS) is a rare severe combined immunodeficiency associated with autoimmunity and caused by defects in lymphoid-specific V(D)J recombination. Most patients carry hypomorphic mutations in recombination-activating gene (RAG) 1 or 2. Hematopoietic stem cell transplantation is the standard treatment; however, gene therapy (GT) might represent a valid alternative, especially for patients lacking a matched donor.
Objective |
We sought to determine the efficacy of lentiviral vector (LV)–mediated GT in the murine model of OS (Rag2R229Q/R229Q) in correcting immunodeficiency and autoimmunity.
Methods |
Lineage-negative cells from mice with OS were transduced with an LV encoding the human RAG2 gene and injected into irradiated recipients with OS. Control mice underwent transplantation with wild-type or OS-untransduced lineage-negative cells. Immunophenotyping, T-dependent and T-independent antigen challenge, immune spectratyping, autoantibody detection, and detailed tissue immunohistochemical analyses were performed.
Results |
LV-mediated GT allowed immunologic reconstitution, although it was suboptimal compared with that seen in wild-type bone marrow (BM)−transplanted OS mice in peripheral blood and hematopoietic organs, such as the BM, thymus, and spleen. We observed in vivo variability in the efficacy of GT correlating with the levels of transduction achieved. Immunoglobulin levels and T-cell repertoire normalized, and gene-corrected mice responded properly to challenges in vivo. Autoimmune manifestations, such as skin infiltration and autoantibodies, dramatically improved in GT mice with a vector copy number/genome higher than 1 in the BM and 2 in the thymus.
Conclusions |
Our data show that LV-mediated GT for patients with OS significantly ameliorates the immunodeficiency, even in an inflammatory environment.
Le texte complet de cet article est disponible en PDF.Key words : Gene therapy, Omenn syndrome, autoimmunity, lentiviral vector, Rag genes
Abbreviations used : AIRE, BAFF, BM, GT, HSCT, Lin−, LV, OS, PID, RAG, SCID, TCR, UCOE, VCN, WT
Plan
| Supported by the Italian Telethon foundation (Telethon Core TGT E2 Grant to A.V.); by the European Commission's 5th, 6th, and 7th and Horizon 2020 Framework Programs (contracts QLK3-CT-2001-00427-INHERINET, LSHB-CT-2004-005242-CONSERT, grant agreement 261387 CELL-PID to A.V. and grant 666908-SCIDNET to A.V.); and by The Netherlands Health Research and Development Organization ZonMw, Translational Gene Therapy Program (project 43100016 to G.W.) and by Italian Ministry of Health (grant GR-2011-02349759 to B.C.). |
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| Disclosure of potential conflict of interest: L. D. Notarangelo is Editor of Frontiers in Immunology, Associate Editor for the Journal of Clinical Immunology, and Associate Editor for Clinical Immunology; is employed by the National Institutes of Health and the Department of Health and Human Services; and has received royalties from UpToDate. G. Wagemaker has received grants and travel support from The Netherlands Organization for Health Research ZonMw and the European Commission. A. Villa has received a grant from the European Commission. The rest of the authors declare that they have no relevant conflict of interest. |
Vol 142 - N° 3
P. 928 - septembre 2018 Retour au numéro
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