5 years of successful inducible transgene expression following locoregional AAV delivery in nonhuman primates with no detectable immunity
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CitationGuilbaud, Mickaël. Devaux, Marie. Couzinié, Celia. Le Duff, Johanne. Toromanoff, Alice. Vandamme, Céline. Jaulin, Nicolas. Gernoux, Gwladys. Larcher, Thibaut. Moullier, Philippe. Le Guiner, Caroline. Adjali, Oumeya. (2019). 5 years of successful inducible transgene expression following locoregional AAV delivery in nonhuman primates with no detectable immunity. Human gene therapy, 30 (7) , 802-813. 10.1089/hum.2018.234.
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.