Safety and Efficacy of Regional Intravenous (RI) Versus Intramuscular (IM) Delivery of rAAV1 and rAAV8 to Nonhuman Primate Skeletal Muscle.
We developed a drug-free regional intravenous (RI) delivery protocol of recombinant adeno-associated virus (rAAV) 1 and 8 to an entire limb in the nonhuman primate (NHP), and compared the results with those produced by intramuscular (IM) delivery of the same dose of vector. We show that RI delivery of both serotypes was remarkably well tolerated with no adverse side-effects. After IM, muscle transduction was restricted to the site of injection with a high number of vector copies per cell for rAAV1. In contrast, although RI delivery resulted in a lower vector copy per cell, it was detectable in the vast majority of muscles of the injected limb. The amounts of circulating infectious rAAV were similar for both serotypes and modes of delivery. At autopsy at up to 34 months after vector administration, similar biodistribution patterns were found for both vectors and for both modes of delivery, with numerous organs found to be positive for vector sequence when assayed using PCR and Southern blot. Altogether, we demonstrated that RI is a simple and efficient transduction protocol in NHPs, resulting in higher expression of the transgene with a lower number of vector genomes per cell. However, regardless of the mode of delivery, concerns continue to be raised by the presence of vector sequences detected at distant sites.
INSERM UMR 649, CHU Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.
Alice
A
Toromanoff
INRA UMR 703, Ecole Nationale Vétérinaire, Nantes, France.
Yan
Y
Chérel
INSERM UMR 649, CHU Nantes, Faculté de Médecine, Université de Nantes, Nantes, France; EFS Pays de la Loire, Nantes, France.
Mickaël
M
Guilbaud
INSERM UMR 649, CHU Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.
Magalie
M
Penaud-Budloo
INSERM UMR 649, CHU Nantes, Faculté de Médecine, Université de Nantes, Nantes, France; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA.
Richard O
RO
Snyder
School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Mark E
ME
Haskins
INRA UMR 703, Ecole Nationale Vétérinaire, Nantes, France; Service des Urgences, Ecole Nationale Vétérinaire, Nantes, France.
Jack-Yves
JY
Deschamps
INRA UMR 703, Ecole Nationale Vétérinaire, Nantes, France.
Lydie
L
Guigand
Service de Chirurgie Pédiatrique, CHU Hôtel-Dieu, Nantes, France.
Guillaume
G
Podevin
The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Valder R
VR
Arruda
The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Howard Hughes Medical Institute, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Katherine A
KA
High
Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Hansell H
HH
Stedman
INSERM UMR 649, CHU Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.
Fabienne
F
Rolling
INSERM UMR 643, CHU Nantes, Institut de Transplantation et de Recherche en Transplantation, Faculté de Médecine, Université de Nantes, Nantes, France.
Ignacio
I
Anegon
INSERM UMR 649, CHU Nantes, Faculté de Médecine, Université de Nantes, Nantes, France; EFS Pays de la Loire, Nantes, France; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA.
Philippe
P
Moullier
INSERM UMR 649, CHU Nantes, Faculté de Médecine, Université de Nantes, Nantes, France. Electronic address: caroline.le-guiner@univ-nantes.fr.
Caroline
C
Le Guiner