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Blood, 1 March 2006, Vol. 107, No. 5, pp. 1810-1817. Prepublished online as a Blood First Edition Paper on October 25, 2005; DOI 10.1182/blood-2005-08-3229. This Article Full Text (PDF) All Versions of this Article: 2005-08-3229v1 107/5/1810    most recent Alert me when this article is cited Alert me if a correction is posted 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 Scallan, C. D Articles by Pierce, G. F Search for Related Content PubMed PubMed Citation Articles by Scallan, C. D Articles by Pierce, G. F Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 12, 2005 Accepted September 29, 2005 Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice Ciaran D Scallan, HAIYAN JIANG*, Tongyao Liu, Susannah Patarroyo-White, Jurg M Sommer, Shangzhen Zhou, Linda B Couto, and Glenn F Pierce Avigen Inc., Alameda, CA, USA * Corresponding author; email: HAIYANJIANG{at}COMCAST.NET. Long term cures of hemophilia B have been achieved using AAV2 delivering the Factor IX gene to the liver of AAV-naive hemophiliac animals. However, the clinical success of this approach requires overcoming pre-existing AAV neutralizing antibodies prevalent in humans. To better define the inhibition of neutralizing antibodies on AAV2-mediated liver transduction, we developed an in vivo passive immunity model. SCID mice were first reconstituted to a defined neutralizing titer with pooled plasma-derived human immunoglobulin. AAV2-FIX vectors were then administered to the liver, and the transduction efficiency was measured by plasma FIX levels. Unexpectedly, AAV2 neutralizing titers lower than 1:10 were sufficient to neutralize 4-20x1012vg/kg of AAV2 vectors in vivo, a capacity that was underestimated by in vitro neutralizing assays. We also evaluated strategies to evade neutralization, including the use of alternative delivery routes, infusion parameters, empty capsids, and alternative AAV serotypes 6 and 8. The results indicate that low AAV2 neutralizing titers can be inhibitory to the tested human and primate AAV vectors delivered into the circulatory system. Therefore, novel non-primate AAV vectors or compartmentalized delivery may offer more consistent therapeutic effects in the presence of pre-existing AAV neutralizing antibodies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: AAV immunity: more than meets the eye David Lillicrap Blood 2006 107: 1741-1742. [Full Text] [PDF] This article has been cited by other articles: J. Lin, R. Calcedo, L. H. Vandenberghe, P. Bell, S. Somanathan, and J. M. Wilson A New Genetic Vaccine Platform Based on an Adeno-Associated Virus Isolated from a Rhesus Macaque J. Virol., December 15, 2009; 83(24): 12738 - 12750. [Abstract] [Full Text] [PDF] L. Yang, J. Jiang, L. M. Drouin, M. Agbandje-Mckenna, C. Chen, C. Qiao, D. Pu, X. Hu, D.-Z. Wang, J. Li, et al. A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection PNAS, March 10, 2009; 106(10): 3946 - 3951. [Abstract] [Full Text] [PDF] A. Negrete and R. M. Kotin Strategies for manufacturing recombinant adeno-associated virus vectors for gene therapy applications exploiting baculovirus technology Brief Funct Genomic Proteomic, July 16, 2008; (2008) eln034v1. [Abstract] [Full Text] [PDF] D. Grimm, J. S. Lee, L. Wang, T. Desai, B. Akache, T. A. Storm, and M. A. Kay In Vitro and In Vivo Gene Therapy Vector Evolution via Multispecies Interbreeding and Retargeting of Adeno-Associated Viruses J. Virol., June 15, 2008; 82(12): 5887 - 5911. [Abstract] [Full Text] [PDF] L. R. Rodino-Klapac, L. G. Chicoine, B. K. Kaspar, and J. R. Mendell Gene Therapy for Duchenne Muscular Dystrophy: Expectations and Challenges Arch Neurol, September 1, 2007; 64(9): 1236 - 1241. [Abstract] [Full Text] [PDF] H. Jiang, L. B. Couto, S. Patarroyo-White, T. Liu, D. Nagy, J. A. Vargas, S. Zhou, C. D. Scallan, J. Sommer, S. Vijay, et al. Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy Blood, November 15, 2006; 108(10): 3321 - 3328. [Abstract] [Full Text] [PDF] T. VandenDriessche CAPitalizing on AAV Blood, July 1, 2006; 108(1): 4 - 5. [Full Text] [PDF] H. Jiang, D. Lillicrap, S. Patarroyo-White, T. Liu, X. Qian, C. D. Scallan, S. Powell, T. Keller, M. McMurray, A. Labelle, et al. Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs Blood, July 1, 2006; 108(1): 107 - 115. [Abstract] [Full Text] [PDF]

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