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Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells.

Authors
  • Pouzolles, Marie1
  • Machado, Alice1
  • Guilbaud, Mickaël2
  • Irla, Magali3
  • Gailhac, Sarah1
  • Barennes, Pierre4
  • Cesana, Daniela5
  • Calabria, Andrea5
  • Benedicenti, Fabrizio5
  • Sergé, Arnauld6
  • Raman, Indu7
  • Li, Quan-Zhen8
  • Montini, Eugenio5
  • Klatzmann, David9
  • Adjali, Oumeya10
  • Taylor, Naomi11
  • Zimmermann, Valérie S12
  • 1 Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France. , (France)
  • 2 INSERM UMR1089, Université de Nantes, Centre Hospitalier Universitaire de Nantes, Nantes, France. , (France)
  • 3 Center of Immunology Marseille-Luminy (CIML), INSERM U1104, CNRS UMR7280, Aix-Marseille Université UM2, Marseille, France. , (France)
  • 4 Sorbonne Université, INSERM, Immunology-Immunopathology-Immunotherapy (i3), Paris, France. , (France)
  • 5 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS, San Raffaele Scientific Institute, Milan, Italy. , (Italy)
  • 6 Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. , (France)
  • 7 Microarray Core Facility, University of Texas Southwestern Medical Center, Dallas, Tex.
  • 8 Microarray Core Facility, University of Texas Southwestern Medical Center, Dallas, Tex; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Tex.
  • 9 Sorbonne Université, INSERM, Immunology-Immunopathology-Immunotherapy (i3), Paris, France; AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (i2B), Paris, France. , (France)
  • 10 INSERM UMR1089, Université de Nantes, Centre Hospitalier Universitaire de Nantes, Nantes, France. Electronic address: [email protected] , (France)
  • 11 Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md. Electronic address: [email protected] , (France)
  • 12 Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France. Electronic address: [email protected] , (France)
Type
Published Article
Journal
The Journal of allergy and clinical immunology
Publication Date
Feb 01, 2020
Volume
145
Issue
2
Identifiers
DOI: 10.1016/j.jaci.2019.08.029
PMID: 31513879
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. 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. 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. Intrathymic AAV-transduced progenitors promote a rapid restoration of the thymic architecture, with a single wave of thymopoiesis generating long-term peripheral T-cell function. Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.

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