Lack of immunotoxicity after regional intravenous (RI) delivery of rAAV to nonhuman primate skeletal muscle.
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.
Toromanoff
Alice
A
INSERM UMR 649, CHU de Nantes, Université de Nantes, Faculté de Médecine, Nantes, France.
Adjali
Oumeya
O
Larcher
Thibaut
T
Hill
Marcelo
M
Guigand
Lydie
L
Chenuaud
Pierre
P
Deschamps
Jack-Yves
JY
Gauthier
Olivier
O
Blancho
Gilles
G
Vanhove
Bernard
B
Rolling
Fabienne
F
Chérel
Yan
Y
Moullier
Philippe
P
Anegon
Ignacio
I
Le Guiner
Caroline
C
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*