title: Lack of immunotoxicity after regional intravenous (RI) delivery of rAAV to nonhuman primate skeletal muscle.
abstract: In the absence of an immune response from the host, intramuscular (IM) injection of recombinant adeno-associated virus (rAAV) results in the permanent expression of the transgene from mouse to primate models. However, recent gene transfer studies into animal models and humans indicate that the risk of transgene and/or capsid-specific immune responses occurs and depends on multiple factors. Among these factors, the route of delivery is important, although poorly addressed in large animal models. Here, we compare the IM and the drug-free regional intravenous (RI) deliveries of rAAV in nonhuman primate (NHP) skeletal muscle monitoring the host immune response toward the transgene. We show that IM is consistently associated with immunotoxicity and the destruction of the genetically modified myofibers, whereas RI allows the stable expression of the transgene. This has important implications for the design of clinical trials for gene transfer in skeletal muscle.
authors.affiliation: INSERM UMR 649, CHU de Nantes, Université de Nantes, Faculté de Médecine, Nantes, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Toromanoff
authors.forename: Oumeya
authors.initials: O
authors.lastname: Adjali
authors.forename: Thibaut
authors.initials: T
authors.lastname: Larcher
authors.forename: Marcelo
authors.initials: M
authors.lastname: Hill
authors.forename: Lydie
authors.initials: L
authors.lastname: Guigand
authors.forename: Pierre
authors.initials: P
authors.lastname: Chenuaud
authors.forename: Jack-Yves
authors.initials: JY
authors.lastname: Deschamps
authors.forename: Olivier
authors.initials: O
authors.lastname: Gauthier
authors.forename: Gilles
authors.initials: G
authors.lastname: Blancho
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
authors.forename: Fabienne
authors.initials: F
authors.lastname: Rolling
authors.forename: Yan
authors.initials: Y
authors.lastname: Chérel
authors.forename: Philippe
authors.initials: P
authors.lastname: Moullier
authors.forename: Ignacio
authors.initials: I
authors.lastname: Anegon
authors.forename: Caroline
authors.initials: C
authors.lastname: Le Guiner
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007273:Injections, Intramuscular / Q000009:adverse effects; D007275:Injections, Intravenous / Q000009:adverse effects*; D008251:Macaca; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic / Q000379:methods*