Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells.
Severe combined immunodeficiency
T-cell reconstitution
gene therapy
humoral immunity
intrathymic gene transfer
medulla formation
thymus
zeta-associated protein of 70kDa
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
06
11
2018
revised:
28
07
2019
accepted:
05
08
2019
pubmed:
13
9
2019
medline:
23
9
2020
entrez:
13
9
2019
Statut:
ppublish
Résumé
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 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 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.
Sections du résumé
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 31513879
pii: S0091-6749(19)31171-6
doi: 10.1016/j.jaci.2019.08.029
pmc: PMC8287836
mid: NIHMS1544020
pii:
doi:
Substances chimiques
ZAP-70 Protein-Tyrosine Kinase
EC 2.7.10.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
679-697.e5Subventions
Organisme : NIAID NIH HHS
ID : R01 AI059349
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011924
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.
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