Open AccessFive Years of Successful Inducible Transgene Expression Following Locoregional Adeno-Associated Virus Delivery in Nonhuman Primates with No Detectable Immunity
Author(s) -
Mickaël Guilbaud,
Marie Françoise Devaux,
Célia Couzinié,
Johanne Le Duff,
Alice Toromanoff,
Céline Vandamme,
Nicolas Jaulin,
Gwladys Gernoux,
Thibaut Larcher,
Philippe Moullier,
Caroline Le Guiner,
Oumeya Adjali
Publication year - 2019
Publication title -
human gene therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.633
H-Index - 149
eISSN - 1557-7422
pISSN - 1043-0342
DOI - 10.1089/hum.2018.234
Subject(s) - transgene , genetic enhancement , biology , adeno associated virus , immunogenicity , gene delivery , immune system , vector (molecular biology) , transactivation , viral vector , immunity , virology , gene expression , immunology , recombinant dna , gene , genetics
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.