title: Safe and efficient transduction of the liver after peripheral vein infusion of self-complementary AAV vector results in stable therapeutic expression of human FIX in nonhuman primates.
abstract: The safety and efficacy of peripheral venous administration of a self-complementary adeno-associated viral vector encoding the human FIX gene (scAAV-LP1-hFIXco) was evaluated in nonhuman primates for gene therapy of hemophilia B. Peripheral vein infusion of 1x10(12) vg/kg scAAV-LP1-hFIXco pseudotyped with serotype 8 capsid, in 3 macaques, resulted in stable therapeutic expression (more than 9 months) of human FIX (hFIX) at levels (1.1+/-0.5 microg/mL, or 22% of normal) that were comparable to those achieved after direct delivery of the same vector dose into the portal circulation (1.3+/-0.3 microg/mL, or 26% of normal). Importantly, the pattern of vector biodistribution after systemic and portal vein administration of scAAV-LP1-hFIXco was almost identical. Additionally, comparable levels of gene transfer were achieved in macaques with preexisting immunity to AAV8 following peripheral vein administration of 1x10(12) vg/kg AAV5-pseudotyped scAAV-LP1-hFIXco. This confirms that alternative serotypes can circumvent preexisting naturally acquired immunity to AAV. Thus, peripheral venous administration of AAV5 and AAV8 vectors is safe and as effective at transducing the liver in nonhuman primates as direct vector administration into the portal circulation. These results should make vector administration to patients, especially those with a severe bleeding diathesis, significantly easier and safer.
authors.affiliation: Department of Haemotology, University College London, UK, and Department of Surgery, St Jude Children's Research Hospital, Memphis, TN, USA. a.nathwani@ucl.ac.uk
authors.forename: Amit C
authors.initials: AC
authors.lastname: Nathwani
authors.forename: John T
authors.initials: JT
authors.lastname: Gray
authors.forename: Jenny
authors.initials: J
authors.lastname: McIntosh
authors.forename: Catherine Y C
authors.initials: CY
authors.lastname: Ng
authors.forename: Junfang
authors.initials: J
authors.lastname: Zhou
authors.forename: Yunyu
authors.initials: Y
authors.lastname: Spence
authors.forename: Melanie
authors.initials: M
authors.lastname: Cochrane
authors.forename: Elaine
authors.initials: E
authors.lastname: Gray
authors.forename: Edward G D
authors.initials: EG
authors.lastname: Tuddenham
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
mesh_terms: D000818:Animals; D000917:Antibody Formation; D005164:Factor IX / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002836:Hemophilia B / Q000628:therapy*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008251:Macaca; D014018:Tissue Distribution; D014161:Transduction, Genetic / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D005164:Factor IX