Five Years of Successful Inducible Transgene Expression Following Locoregional Adeno-Associated Virus Delivery in Nonhuman Primates with No Detectable Immunity

Hum Gene Ther. 2019 Jul;30(7):802-813. doi: 10.1089/hum.2018.234. Epub 2019 Apr 16.


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.

Keywords: AAV; gene transfer; immunogenicity; locoregional delivery; long-term follow-up; nonhuman primate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Viral / immunology
  • Cytokines / metabolism
  • Dependovirus / genetics*
  • Dependovirus / immunology
  • Follow-Up Studies
  • Gene Expression*
  • Gene Transfer Techniques*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / adverse effects
  • Genetic Vectors / genetics*
  • Genome, Viral
  • Immunity
  • Macaca fascicularis
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Time Factors
  • Transgenes*


  • Antibodies, Viral
  • Cytokines