AAV8 locoregional delivery induces long-term expression of an immunogenic transgene in macaques despite persisting local inflammation.

Autor:	Gernoux G; Université de Nantes, CHU de Nantes, INSERM UMR 1089, Translational Gene Therapy for Genetic Diseases, 44200 Nantes, France., Guilbaud M; Université de Nantes, CHU de Nantes, INSERM UMR 1089, Translational Gene Therapy for Genetic Diseases, 44200 Nantes, France., Devaux M; Université de Nantes, CHU de Nantes, INSERM UMR 1089, Translational Gene Therapy for Genetic Diseases, 44200 Nantes, France., Journou M; Université de Nantes, CHU de Nantes, INSERM UMR 1089, Translational Gene Therapy for Genetic Diseases, 44200 Nantes, France., Pichard V; Université de Nantes, CHU de Nantes, INSERM UMR 1089, Translational Gene Therapy for Genetic Diseases, 44200 Nantes, France., Jaulin N; Université de Nantes, CHU de Nantes, INSERM UMR 1089, Translational Gene Therapy for Genetic Diseases, 44200 Nantes, France., Léger A; Université de Nantes, CHU de Nantes, INSERM UMR 1089, Translational Gene Therapy for Genetic Diseases, 44200 Nantes, France., Le Duff J; Université de Nantes, CHU de Nantes, INSERM UMR 1089, Translational Gene Therapy for Genetic Diseases, 44200 Nantes, France., Deschamps JY; Centre de Boisbonne, ONIRIS, 44307 Nantes, France., Le Guiner C; Université de Nantes, CHU de Nantes, INSERM UMR 1089, Translational Gene Therapy for Genetic Diseases, 44200 Nantes, France., Moullier P; Université de Nantes, CHU de Nantes, INSERM UMR 1089, Translational Gene Therapy for Genetic Diseases, 44200 Nantes, France., Cherel Y; INRA UMR 703, PAnTher, ONIRIS, 44307 Nantes, France., Adjali O; Université de Nantes, CHU de Nantes, INSERM UMR 1089, Translational Gene Therapy for Genetic Diseases, 44200 Nantes, France.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2021 Feb 06; Vol. 20, pp. 660-674. Date of Electronic Publication: 2021 Feb 06 (Print Publication: 2021).
DOI:	10.1016/j.omtm.2021.02.003
Abstrakt:	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 long-term 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. Competing Interests: G.G., M.G., M.D., N.J., V.P., M.J., A.L., J.L.D., J.-Y.D., C.L.G., P.M., Y.C., and O.A. declare no competing interests. P.M. is an employee of Asklepios BioPharmaceutical. (© 2021.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu