title: Safety and efficacy of regional intravenous (r.i.) versus intramuscular (i.m.) delivery of rAAV1 and rAAV8 to nonhuman primate skeletal muscle.
abstract: We developed a drug-free regional intravenous (r.i.) 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 (i.m.) delivery of the same dose of vector. We show that r.i. delivery of both serotypes was remarkably well tolerated with no adverse side-effects. After i.m., muscle transduction was restricted to the site of injection with a high number of vector copies per cell for rAAV1. In contrast, although r.i. 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 r.i. 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.
authors.affiliation: INSERM UMR 649, CHU Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Toromanoff
authors.forename: Yan
authors.initials: Y
authors.lastname: Chérel
authors.forename: Mickaël
authors.initials: M
authors.lastname: Guilbaud
authors.forename: Magalie
authors.initials: M
authors.lastname: Penaud-Budloo
authors.forename: Richard O
authors.initials: RO
authors.lastname: Snyder
authors.forename: Mark E
authors.initials: ME
authors.lastname: Haskins
authors.forename: Jack-Yves
authors.initials: JY
authors.lastname: Deschamps
authors.forename: Lydie
authors.initials: L
authors.lastname: Guigand
authors.forename: Guillaume
authors.initials: G
authors.lastname: Podevin
authors.forename: Valder R
authors.initials: VR
authors.lastname: Arruda
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
authors.forename: Hansell H
authors.initials: HH
authors.lastname: Stedman
authors.forename: Fabienne
authors.initials: F
authors.lastname: Rolling
authors.forename: Ignacio
authors.initials: I
authors.lastname: Anegon
authors.forename: Philippe
authors.initials: P
authors.lastname: Moullier
authors.forename: Caroline
authors.initials: C
authors.lastname: Le Guiner
mesh_terms: D000818:Animals; D004279:DNA, Viral / Q000097:blood; D000229:Dependovirus; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007273:Injections, Intramuscular / Q000009:adverse effects; D007275:Injections, Intravenous / Q000009:adverse effects; D008252:Macaca fascicularis; D008297:Male; D018482:Muscle, Skeletal; D014161:Transduction, Genetic / Q000379:methods*; D019076:Transgenes
chemical_list: D004279:DNA, Viral