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Prepublished online as a Blood First Edition Paper on March 13, 2003; DOI 10.1182/blood-2002-09-2889. This Article Full Text (PDF) All Versions of this Article: 2002-09-2889v1 102/2/480    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 Davidoff, A. M Articles by Nathwani, A. C Search for Related Content PubMed PubMed Citation Articles by Davidoff, A. M Articles by Nathwani, A. C Social Bookmarking                   What's this? Submitted September 23, 2002 Accepted February 24, 2003 Gender significantly influences transduction of murine liver by recombinant adeno-associated viral vectors through an androgen-dependent pathway Andrew M Davidoff*, Catherine Y C Ng, Junfang Zhou, Yunyu Spence, and Amit C Nathwani Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA Division of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA Department of Haematology, University College London, London, United Kingdom National Blood Service, London, United Kingdom * Corresponding author; email: andrew.davidoff{at}stjude.org. A systematic evaluation of the influence of gender on transduction by recombinant adeno-associated viral vector (rAAV) indicated that transgene expression after liver targeted delivery of vector particles was between 5-13 fold higher in male mice compared to females, irrespective of the proviral promoter or cDNA and mouse strain. Molecular analysis revealed that the rAAV genome was stably retained in male liver at levels that were 7-fold higher than those observed in females. Further, the gender difference in transduction was observed with AAV2 and AAV5 based vectors, which utilize distinct receptor complexes for infection. In concordance with the differences in AAV transduction, gel shift analysis with nuclear extracts derived from the liver of mice and humans, revealed substantially higher binding of host nuclear protein to the rep-binding site (RBS) of AAV ITR in males compared to females. Transduction efficiency and binding of nuclear protein to RBS was dramatically reduced in male mice by castration. In contrast, although oophorectomy did not significantly influence rAAV transduction, administration of 5 dihydrotestosterone, prior to gene transfer, increased stable hepatocyte gene transfer in females to levels observed in male mice, implying that androgens significantly influence hepatocyte gene transfer. Interestingly, gender did not have a significant impact on AAV gene transfer into non-hepatic tissue indicating that there are distinct tissue and gender specific differences in the mechanisms responsible for efficient transduction with this vector. These results have significant implications for gene therapy of autosomal and acquired disorders affecting the liver. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. J. Ho, C. E. Bass, A. H. K. Kroemer, C. Ma, E. Terwilliger, and S. J. Karp Optimized adeno-associated virus 8 produces hepatocyte-specific Cre-mediated recombination without toxicity or affecting liver regeneration Am J Physiol Gastrointest Liver Physiol, August 1, 2008; 295(2): G412 - G419. [Abstract] [Full Text] [PDF] P. V. Dickson, J. B. Hamner, C. J. Streck, C. Y.C. Ng, M. B. McCarville, C. Calabrese, R. J. Gilbertson, C. F. Stewart, C. M. Wilson, M. W. Gaber, et al. Continuous Delivery of IFN-{beta} Promotes Sustained Maturation of Intratumoral Vasculature Mol. Cancer Res., June 1, 2007; 5(6): 531 - 542. [Abstract] [Full Text] [PDF] A. C. Nathwani, J. T. Gray, C. Y. C. Ng, J. Zhou, Y. Spence, S. N. Waddington, E. G. D. Tuddenham, G. Kemball-Cook, J. McIntosh, M. Boon-Spijker, et al. Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver Blood, April 1, 2006; 107(7): 2653 - 2661. [Abstract] [Full Text] [PDF] C. J. Streck, P. V. Dickson, C. Y.C. Ng, J. Zhou, J. T. Gray, A. C. Nathwani, and A. M. Davidoff Adeno-Associated Virus Vector-Mediated Systemic Delivery of IFN-{beta} Combined with Low-Dose Cyclophosphamide Affects Tumor Regression in Murine Neuroblastoma Models Clin. Cancer Res., August 15, 2005; 11(16): 6020 - 6029. [Abstract] [Full Text] [PDF] L. Wang, R. Calcedo, T. C. Nichols, D. A. Bellinger, A. Dillow, I. M. Verma, and J. M. Wilson Sustained correction of disease in naive and AAV2-pretreated hemophilia B dogs: AAV2/8-mediated, liver-directed gene therapy Blood, April 15, 2005; 105(8): 3079 - 3086. [Abstract] [Full Text] [PDF]

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