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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1414-1421. Prepublished online as a Blood First Edition Paper on November 7, 2006; DOI 10.1182/blood-2006-03-010181. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-03-010181v1 109/4/1414    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nathwani, A. C. Articles by Davidoff, A. M. Search for Related Content PubMed PubMed Citation Articles by Nathwani, A. C. Articles by Davidoff, A. M. Related Collections Hemostasis, Thrombosis, and Vascular Biology Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY 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. Nathwani1,2, John T. Gray3, Jenny McIntosh1, Catherine Y. C. Ng4, Junfang Zhou4, Yunyu Spence4, Melanie Cochrane1, Elaine Gray5, Edward G. D. Tuddenham1,6, and Andrew M. Davidoff3,4 1 Department of Haematology, University College London and 2 National Blood Service, United Kingdom; 3 Division of Experimental Hematology and 4 Department of Surgery, St Jude Children's Research Hospital, Memphis, TN; 5 Department of Haematology, National Institute for Biological Standards and Control, Potters Bar, United Kingdom; and 6 Katharine Dormandy Haemophilia Centre, London, United Kingdom 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 1 x 1012 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 µg/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 µg/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 1 x 1012 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. H. Tan, A. J. Smith, B. Pawlyk, X. Xu, X. Liu, J. B. Bainbridge, M. Basche, J. McIntosh, H. V. Tran, A. Nathwani, et al. Gene therapy for retinitis pigmentosa and Leber congenital amaurosis caused by defects in AIPL1: effective rescue of mouse models of partial and complete Aipl1 deficiency using AAV2/2 and AAV2/8 vectors Hum. Mol. Genet., June 15, 2009; 18(12): 2099 - 2114. [Abstract] [Full Text] [PDF] F. Mingozzi, N. C. Hasbrouck, E. Basner-Tschakarjan, S. A. Edmonson, D. J. Hui, D. E. Sabatino, S. Zhou, J. F. Wright, H. Jiang, G. F. Pierce, et al. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver Blood, October 1, 2007; 110(7): 2334 - 2341. [Abstract] [Full Text] [PDF] T. Ito, T. Okada, J. Mimuro, H. Miyashita, R. Uchibori, M. Urabe, H. Mizukami, A. Kume, M. Takahashi, U. Ikeda, et al. Adenoassociated Virus Mediated Prostacyclin Synthase Expression Prevents Pulmonary Arterial Hypertension in Rats Hypertension, September 1, 2007; 50(3): 531 - 536. [Abstract] [Full Text] [PDF] K. A. High Update on Progress and Hurdles in Novel Genetic Therapies for Hemophilia Hematology, January 1, 2007; 2007(1): 466 - 472. [Abstract] [Full Text] [PDF]

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