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

M. Pouzolles,Alice Machado,Mickaël Guilbaud,M. Irla,S. Gailhac,P. Barennes,D. Cesana,A. Calabria,F. Benedicenti,Arnauld Sergé,Indu Raman,Quanzhen Li,E. Montini,D. Klatzmann,O. Adjali,N. Taylor,V. Zimmermann

Published 2020 in Journal of Allergy and Clinical Immunology

ABSTRACT

BACKGROUND Patients with T cell immunodeficiencies are generally treated by allogeneic hematopoietic stem cell transplantation but alternatives are needed for patients without matched donors. An innovative intrathymic (IT) gene therapy approach, directly targeting the thymus, may improve outcome. OBJECTIVE To determine the efficacy of IT-adeno-associated virus (AAV) serotypes to transduce thymocyte subsets and correct the T cell immunodeficiency in a ZAP-70-deficient murine model. METHODS AAV serotypes were injected intrathymically into WT mice and gene transfer efficiency was monitored. ZAP-70-/- mice were intrathymically injected with an AAV8 vector harboring the ZAP-70 gene. Thymus structure, immunophenotyping, TCR clonotypes, T cell function, immune responses to transgenes and autoantibodies, vector copy number and integration were evaluated. RESULTS AAV 8, 9 and 10 serotypes all transduced thymocyte subsets following in situ gene transfer, with transduction of up to 5% of cells. IT 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 AIRE were detected within 10 days of gene transfer, correlating with the presence of functional effector and regulatory T cell subsets with diverse TCR clonotypes in the periphery. While thymocyte reconstitution was transient, gene-corrected peripheral T cells, harboring approximately 1 AAV genome/ cell, persisted for >40 weeks and AAV vector integration was detected. CONCLUSIONS Intrathymic AAV-transduced progenitors promote a rapid restoration of the thymus architecture with a single wave of thymopoiesis generating long-term peripheral T cell function.

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