AAV8 locoregional delivery induces long-term expression of an immunogenic transgene in macaques despite persisting local inflammation
| العنوان: | AAV8 locoregional delivery induces long-term expression of an immunogenic transgene in macaques despite persisting local inflammation |
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| المؤلفون: | Virginie Pichard, Oumeya Adjali, Nicolas Jaulin, Malo Journou, Johanne Le Duff, Gwladys Gernoux, Adrien Leger, Caroline Le Guiner, Yan Cherel, Marie Devaux, Mickaël Guilbaud, Jack-Yves Deschamps, Philippe Moullier |
| المساهمون: | 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), JAULIN, Nicolas, Blanc - INDUCTION DE TOLERANCE SPECIFIQUE DU TRANSGENE APRES THERAPIE GENIQUE - - GENETOL2009 - ANR-09-BLAN-0265 - Blanc - VALID, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, Transfert de gène dans le muscle squelettique à l'aide d'AAV: Décryptage de la réponse immune de l'hôte - - TOLGEN2017 - ANR-17-CE17-0007 - AAPG2017 - VALID, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) |
| المصدر: | Molecular Therapy: Methods & Clinical Development, Vol 20, Iss, Pp 660-674 (2021) Molecular Therapy-Methods and Clinical Development Molecular Therapy-Methods and Clinical Development, Nature Publishing Group, 2021, 20, pp.660-674. ⟨10.1016/j.omtm.2021.02.003⟩ Molecular Therapy. Methods & Clinical Development |
| بيانات النشر: | Elsevier BV, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, regulatory T cell, lcsh:QH426-470, macaques, Regulatory T cell, [SDV]Life Sciences [q-bio], Transgene, locoregional delivery, Inflammation, immune response, Virus, Green fluorescent protein, 03 medical and health sciences, Transduction (genetics), 0302 clinical medicine, Immune system, Genetics, medicine, Vector (molecular biology), lcsh:QH573-671, tolerance, gene transfer, Molecular Biology, lcsh:Cytology, business.industry, AAV, 3. Good health, [SDV] Life Sciences [q-bio], Treg, lcsh:Genetics, 030104 developmental biology, medicine.anatomical_structure, inflammation, 030220 oncology & carcinogenesis, Immunology, Molecular Medicine, Original Article, medicine.symptom, business |
| الوصف: | 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. Graphical Abstract Immune responses can be a major limit to rAAV gene transfer efficiency. Gernoux et al. show that locoregional intravenous perfusion (LR) of an AAV8 vector encoding for the highly immunogenic GFP protein in monkeys leads to persisting transgene expression. The inflammation observed in situ is balanced by regulatory T cells. |
| وصف الملف: | application/pdf |
| تدمد: | 2329-0501 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ddc7495eb50c9a410c7de397d4680321Test https://doi.org/10.1016/j.omtm.2021.02.003Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ddc7495eb50c9a410c7de397d4680321 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23290501 |
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