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Prepublished online as a Blood First Edition Paper on May 17, 2002; DOI 10.1182/blood-2002-02-0589.
Submitted February 22, 2002
Accepted April 30, 2002
SUSTAINED HIGH LEVEL EXPRESSION OF HUMAN FIX FOLLOWING LIVER TARGETED DELIVERY OF RECOMBINANT ADENO-ASSOCIATED VIRUS ENCODING THE HUMAN FIX GENE IN RHESUS MACAQUES
Amit C Nathwani, Andrew M Davidoff, Hideki Hanawa, Yunyu Hu, Fredric A Hoffer, Alexander Nikanorov, Clive Slaughter, Catherine Y Ng, Junfang Zhou, Jay N Lozier, Timothy D Mandrell, Elio F Vanin, and Arthur W Nienhuis*
Department of Haematology, University College London and National Blood Authority, London, United Kingdom
Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Division of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA
Department of Comparative Medicine, University of Tennessee, Health Science Center, Memphis, Tennessee, USA
* Corresponding author; email: arthur.nienhuis{at}stjude.org.
In this study, the feasibility, safety and efficacy of liver-directed gene transfer was evaluated in five male macaques between the ages of 2.5 to 6.5 years using a recombinant adeno-associated viral (rAAV) vector, rAAV-2 CAGG-hFIX, that had previously mediated persistent therapeutic expression of human FIX (hFIX) (6-10% of physiological levels) in murine models. A dose of 4 x 1012 vg/kg was administered via the hepatic artery or portal vein. Persistence of the rAAV vector genome as circular monomers and dimers and high molecular weight concatamers was documented by Southern blot analysis in liver for periods up to 1 year. Vector particles were present in plasma, urine or saliva for several days post infusion as shown by PCR and the vector genome was detected in spleen at low copy numbers. An enzyme linked immunosorption assay (ELISA) capable of detecting between 1 and 25% of normal levels of hFIX in rhesus plasma was developed using hyperimmune serum from a rhesus monkey that had received an adenoviral vector encoding hFIX. Two animals having 3 or 40 rAAV genome equivalents per cell in liver had 4% or 8% of normal physiological levels of hFIX in plasma. A level of hFIX of 3% of normal was transiently detected in one other animal which had a genome copy number of 25 prior to abrogation by a neutralizing antibody (inhibitor) to hFIX. This nonhuman primate model will be highly useful in further evaluation and development of rAAV vectors for gene therapy of hemophilia B.
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