Intrathymic AAV delivery results in therapeutic site-specific integration at TCR loci in mice.

Autor:	Calabria A; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Cipriani C; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Spinozzi G; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Rudilosso L; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Esposito S; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Benedicenti F; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Albertini A; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Pouzolles M; Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique (CNRS), Paris, France., Luoni M; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy., Giannelli S; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy., Broccoli V; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Neuroscience Institute, National Research Council of Italy, Milan, Italy., Guilbaud M; Translational Gene Therapy Laboratory, INSERM and Nantes University, Nantes, France., Adjali O; Translational Gene Therapy Laboratory, INSERM and Nantes University, Nantes, France., Taylor N; Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique (CNRS), Paris, France.; Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD., Zimmermann VS; Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique (CNRS), Paris, France., Montini E; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy., Cesana D; San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2023 May 11; Vol. 141 (19), pp. 2316-2329.
DOI:	10.1182/blood.2022017378
Abstrakt:	Adeno-associated virus (AAV) vectors have been successfully exploited in gene therapy applications for the treatment of several genetic disorders. AAV is considered an episomal vector, but it has been shown to integrate within the host cell genome after the generation of double-strand DNA breaks or nicks. Although AAV integration raises some safety concerns, it can also provide therapeutic benefit; the direct intrathymic injection of an AAV harboring a therapeutic transgene results in integration in T-cell progenitors and long-term T-cell immunity. To assess the mechanisms of AAV integration, we retrieved and analyzed hundreds of AAV integration sites from lymph node-derived mature T cells and compared these with liver and brain tissue from treated mice. Notably, we found that although AAV integrations in the liver and brain were distributed across the entire mouse genome, >90% of the integrations in T cells were clustered within the T-cell receptor α, β, and γ genes. More precisely, the insertion mapped to DNA breaks created by the enzymatic activity of recombination activating genes (RAGs) during variable, diversity, and joining recombination. Our data indicate that RAG activity during T-cell receptor maturation induces a site-specific integration of AAV genomes and opens new therapeutic avenues for achieving long-term AAV-mediated gene transfer in dividing cells. (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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