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

Human Gene Therapy
Mickaël GuilbaudOumeya Adjali

Abstract

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 s...Continue Reading

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Citations

Apr 5, 2019·Molecular Diagnosis & Therapy·Petros PatsaliCarsten W Lederer
Jul 2, 2019·Human Molecular Genetics·Claire Domenger, Dirk Grimm
Apr 8, 2020·Frontiers in Immunology·José M Martinez-NavioRonald C Desrosiers
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Mar 16, 2021·Molecular Therapy. Methods & Clinical Development·Gwladys GernouxOumeya Adjali
May 2, 2020·Molecular Therapy. Methods & Clinical Development·Karim BeyMarie-Anne Colle
May 4, 2021·Frontiers in Cell and Developmental Biology·Marisa CappellaMaria Grazia Biferi
Jan 8, 2020·Molecular Therapy. Methods & Clinical Development·Michaël HocquemillerRalph Laufer
Jan 24, 2020·Molecular Therapy. Methods & Clinical Development·Ashley T Martino, David M Markusic
Oct 16, 2021·Proceedings of the National Academy of Sciences of the United States of America·Qiang WangSai-Juan Chen

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Methods Mentioned

BETA
biopsies
enzyme-linked immunosorbent assay
ELISA
light microscopy
PCR

Software Mentioned

AID ELISpot Reader

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