AAV8 locoregional delivery induces long-term expression of an immunogenic transgene in macaques despite persisting local inflammation
In: ISSN: 2329-0501 ; Molecular Therapy - Methods and Clinical Development ; https://www.hal.inserm.fr/inserm-03172941 ; Molecular Therapy - Methods and Clinical Development, Nature Publishing Group, 2021, 2021
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Zugriff:
International audience ; Adeno-associated virus (AAV) vectors are considered efficient vectors for gene transfer, as illustrated by recent successful clinical trials targeting retinal or neurodegenerative disorders. However, limitations as host immune responses to AAV capsid or transduction of limited regions must still be overcome. Here, we focused on locoregional (LR) intravenous perfusion vector delivery that allows transduction of large muscular areas and is considered to be less immunogenic than intramuscular (IM) injection. To confirm this hypothesis, we injected 6 cynomolgus monkeys with an AAV serotype 8 (AAV8) vector encoding for the highly immunogenic GFP driven by either a muscle-specific promoter (n = 3) or a cytomegalovirus (CMV) promoter (n = 3). We report that LR delivery allows longterm GFP expression in the perfused limb (up to 1 year) despite the initiation of a peripheral transgene-specific immune response. The analysis of the immune status of the perfused limb shows that LR delivery induces persisting inflammation. However, this inflammation is not sufficient to result in transgene clearance and is balanced by resident regulatory T cells. Overall, our results suggest that LR delivery promotes persisting transgene expression by induction of Treg cells in situ and might be a safe alternative to IM route to target large muscle territories for the expression of secreted therapeutic factors.
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AAV8 locoregional delivery induces long-term expression of an immunogenic transgene in macaques despite persisting local inflammation
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Autor/in / Beteiligte Person: | Gernoux, Gwladys ; Guilbaud, Mickaël ; Devaux, Marie ; Journou, Malo ; Pichard, Virginie ; Jaulin, Nicolas ; Léger, Adrien ; Le Duff, Johanne ; Deschamps, Jack-Yves ; Le Guiner, Caroline ; Moullier, Philippe ; Cherel, Yan ; Adjali, Oumeya ; 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 de Boisbonne Nantes ; Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS) ; Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher) ; Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) ; Institut National de la Sante et de la Recherche Medicale (Inserm)European CommissionCHU de NantesEuropean CommissionAFM-Telethon (Association Francaise contre les Myopathies)Appeared in source as:National Research AgencyRegion Pays de la LoireRegion Pays de la Loire ; ANR-09-BLAN-0265,GENETOL,INDUCTION DE TOLERANCE SPECIFIQUE DU TRANSGENE APRES THERAPIE GENIQUE(2009) ; ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010) ; ANR-17-CE17-0007,TOLGEN,Transfert de gène dans le muscle squelettique à l'aide d'AAV: Décryptage de la réponse immune de l'hôte(2017) |
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Zeitschrift: | ISSN: 2329-0501 ; Molecular Therapy - Methods and Clinical Development ; https://www.hal.inserm.fr/inserm-03172941 ; Molecular Therapy - Methods and Clinical Development, Nature Publishing Group, 2021, 2021 |
Veröffentlichung: | HAL CCSD ; Nature Publishing Group, 2021 |
Medientyp: | academicJournal |
DOI: | 10.1016/j.omtm.2021.02.003 |
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