Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells
In: ISSN: 0091-6749 ; Journal of Allergy and Clinical Immunology ; https://hal.science/hal-02350097 ; Journal of Allergy and Clinical Immunology, 2020, 145 (2), pp.679-697.e5. ⟨10.1016/j.jaci.2019.08.029⟩, 2020
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Referred to by : Gregori Silvia, Aiuti Alessandro - Intrathymic delivery a new route for adenoviral-associated vector gene therapy - Journal of Allergy and Clinical Immunology, Volume 145, Issue 2, February 2020, Pages 499-501 ; International audience ; BACKGROUND: Patients with T-cell immunodeficiencies are generally treated with allogeneic hematopoietic stem cell transplantation, but alternatives are needed for patients without matched donors. An innovative intrathymic gene therapy approach that directly targets the thymus might improve outcomes.OBJECTIVE: We sought to determine the efficacy of intrathymic adeno-associated virus (AAV) serotypes to transduce thymocyte subsets and correct the T-cell immunodeficiency in a zeta-associated protein of 70 kDa (ZAP-70)-deficient murine model.METHODS: AAV serotypes were injected intrathymically into wild-type mice, and gene transfer efficiency was monitored. ZAP-70-/- mice were intrathymically injected with an AAV8 vector harboring the ZAP70 gene. Thymus structure, immunophenotyping, T-cell receptor clonotypes, T-cell function, immune responses to transgenes and autoantibodies, vector copy number, and integration were evaluated.RESULTS: AAV8, AAV9, and AAV10 serotypes all transduced thymocyte subsets after in situ gene transfer, with transduction of up to 5% of cells. Intrathymic injection of an AAV8-ZAP-70 vector into ZAP-70-/- mice resulted in a rapid thymocyte differentiation associated with the development of a thymic medulla. Strikingly, medullary thymic epithelial cells expressing the autoimmune regulator were detected within 10 days of gene transfer, correlating with the presence of functional effector and regulatory T-cell subsets with diverse T-cell receptor clonotypes in the periphery. Although thymocyte reconstitution was transient, gene-corrected peripheral T cells harboring approximately 1 AAV genome per cell persisted for more than 40 weeks, and AAV vector integration was detected.CONCLUSIONS: Intrathymic AAV-transduced progenitors promote a rapid ...
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Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells
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Autor/in / Beteiligte Person: | Pouzolles, Marie ; Machado, Alice ; Guilbaud, Mickaël ; Irla, Magali ; Gailhac, Sarah ; Barennes, Pierre ; Cesana, Daniela ; Calabria, Andrea ; Benedicenti, Fabrizio ; Sergé, Arnauld ; Raman, Indu ; Li, Quan-Zhen ; Montini, Eugenio ; Klatzmann, David ; Adjali, Oumeya ; Taylor, Naomi ; Zimmermann, Valérie ; Institut de Génétique Moléculaire de Montpellier (IGMM) ; Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) ; Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE) ; Université de Nantes (UN)-Université de Nantes (UN) ; Centre d'Immunologie de Marseille - Luminy (CIML) ; Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) ; Immunologie - Immunopathologie - Immunothérapie CHU Pitié Salpêtrière (I3) ; CHU Charles Foix AP-HP ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière AP-HP ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU) ; IRCCS San Raffaele Scientific Institute Milan, Italie ; Centre de Recherche en Cancérologie de Marseille (CRCM) ; Aix Marseille Université (AMU)-Institut Paoli-Calmettes (IPC) ; Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) ; University of Texas Southwestern Medical Center Dallas ; Centre d'investigation clinique Biothérapie CHU Pitié-Salpêtrière (CIC-BTi) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière AP-HP ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU) ; CHU Pitié-Salpêtrière AP-HP ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU) ; National Cancer Institute Bethesda (NCI-NIH) ; National Institutes of Health Bethesda, MD, USA (NIH) ; M.P. was supported by a PhD fellowship from the LABEX EpiGenMed and the FRM. M.I. and O.A. are supported by INSERM, N.T. was supported by INSERM and the National Institutes of Health, and V.S.Z. is supported by CNRS. This work was funded by the AFM, grant R01AI059349 from the National Institute of Allergy and Infectious Diseases, and the ANR, ARC, FRM, INCA, and ERC-Advanced TRiPoD (#322856 to D.K.). ; ANR-16-RHUS-0001,iMAP,iMAP(2016) |
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Zeitschrift: | ISSN: 0091-6749 ; Journal of Allergy and Clinical Immunology ; https://hal.science/hal-02350097 ; Journal of Allergy and Clinical Immunology, 2020, 145 (2), pp.679-697.e5. ⟨10.1016/j.jaci.2019.08.029⟩, 2020 |
Veröffentlichung: | HAL CCSD ; Elsevier, 2020 |
Medientyp: | academicJournal |
DOI: | 10.1016/j.jaci.2019.08.029 |
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