Submitted March 16, 2006
Accepted August 25, 2006
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
Amit C Nathwani*, John T Gray, Jenny McIntosh, Catherine Y.C. Ng, Junfang Zhou, Yunyu Spence, Melanie Cochrane, Elaine Gray, Edward G. D. Tuddenham, and Andrew M. Davidoff
National Blood Service, United Kingdom
St. Jude Children's Research Hospital, United States
University College London, United Kingdom
National Institute for Biological Standards and Control, United Kingdom
Katharine Dormandy Haemophilia Centre, United Kingdom
* Corresponding author; email: a.nathwani{at}ucl.ac.uk.
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 1x1012vg/kg of scAAV-LP1-hFIXco pseudotyped with serotype-8 capsid, in three macaques, resulted in stable therapeutic expression (>9 months) of human FIX (hFIX) at levels (1.1±0.5µg/ml [22% of normal]) that were comparable to those achieved after direct delivery of the same vector dose into the portal circulation (1.3±0.3µg/ml [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 pre-existing immunity to AAV8 following peripheral vein administration of 1x1012 vg/kg of AAV5-pseudotyped scAAV-LP1-hFIXco. This confirms that alternative serotypes can circumvent pre-existing naturally acquired immunity to AAV. Thus peripheral venous administration of AAV5 and 8 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.
