Journal
HUMAN GENE THERAPY
Volume 30, Issue 7, Pages 802-813Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2018.234
Keywords
AAV; gene transfer; locoregional delivery; nonhuman primate; immunogenicity; long-term follow-up
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Funding
- INSERM
- CHU de Nantes
- Fondation pour la Therapie Genique en Pays de Loire
- AFM-Telethon (Association Francaise contre les Myopathies)
- National Research Agency [ANR-09-BLAN-0265]
- Region Pays de La Loire
- French government [ANR-10-IBHU-005]
- Nantes Metropole
- Agence Nationale de la Recherche (ANR) [ANR-09-BLAN-0265] Funding Source: Agence Nationale de la Recherche (ANR)
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Anti-transgene immune responses elicited after intramuscular (i.m.) delivery of recombinant adeno-associated virus (rAAV) have been shown to hamper long-term transgene expression in large-animal models of rAAV-mediated gene transfer. To overcome this hurdle, an alternative mode of delivery of rAAV vectors in nonhuman primate muscles has been described: the locoregional (LR) intravenous route of administration. Using this injection mode, persistent inducible transgene expression for at least 1 year under the control of the tetracycline-inducible Tet-On system was previously reported in cynomolgus monkeys, with no immunity against the rtTA transgene product. The present study shows the long-term follow-up of these animals. It is reported that LR delivery of a rAAV2/1 vector allows long-term inducible expression up to at least 5 years post gene transfer, with no any detectable host immune response against the transactivator rtTA, despite its immunogenicity following i.m. gene transfer. This study shows for the first time a long-term regulation of muscle gene expression using a Tet-On-inducible system in a large-animal model. Moreover, these findings further confirm that the rAAV LR delivery route is efficient and immunologically safe, allowing long-term skeletal muscle gene transfer.
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