SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on May 22, 2003; DOI 10.1182/blood-2003-01-0167. This Article Full Text (PDF) All Versions of this Article: 2003-01-0167v1 102/6/2038    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 Powell, J. S Articles by Hurst, D. Search for Related Content PubMed PubMed Citation Articles by Powell, J. S Articles by Hurst, D. Social Bookmarking                   What's this? Submitted January 21, 2003 Accepted May 5, 2003 Phase I trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion Jerry S Powell*, Margaret V Ragni, Gilbert C White, Jeanne M Lusher, Carol Hillman-Wiseman, Tom E Moon, Veronica Cole, Sandhya Ramanathan-Girish, Holger Roehl, Nancy Sajjadi, Douglas J Jolly, and Deborah Hurst Department of Internal Medicine, Univ. of California at Davis, Sacramento, CA, USA Department of Pediatrics, Univ. of Pittsburgh, Pittsburgh, PA, USA Department of Pediatrics, Univ. of North Carolina, Chapel Hill, NC, USA Department of Pediatrics, Wayne State Univ., Detroit, MI, USA Department of Gene Therapy, Chiron Corp., Emeryville, CA, USA Department of Gene Therapy, Chiron Corp, San Diego, CA, USA Cell Genesys, San Diego, CA, USA Biomedica Inc, San Diego, CA, USA Sajjadi Associates, Encinitis, CA, USA * Corresponding author; email: jspowell{at}ucdavis.edu. In a phase I dose escalation study, 13 subjects with hemophilia A received by peripheral intravenous infusion a retroviral vector carrying a B-domain deleted human factor VIII gene. Infusions were well tolerated. Tests for replication competent retrovirus have been negative. PCR analyses demonstrate the persistence of vector gene sequences in peripheral blood mononuclear cells in 3 of 3 subjects tested. Factor VIII was measured in serial samples using both a one stage clotting assay and a chromogenic assay. While no subject had sustained FVIII increases, nine subjects had FVIII > 1% on at least two occasions five or more days after infusion of exogenous FVIII, with isolated levels that ranged from 2.3 to 19%. Pharmacokinetic parameters of exogenous FVIII infused into subjects 13 weeks after vector infusion showed an increased half-life (T1/2, p<0.02) and area under the curve (AUC, p<0.04) compared to pre-study values. Bleeding frequency decreased in 5 subjects compared to historical rates. These results demonstrate that this retroviral vector (hFVIII(V)) is safe and, in some subjects, persists up to a year in peripheral blood mononuclear cells, with measurable Factor VIII levels and with increased available FVIII activity (increased T1/2 and AUC) after infusion of exogenous FVIII concentrate. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. Peng, P. Ye, D. J. Rawlings, H. D. Ochs, and C. H. Miao Anti-CD3 antibodies modulate anti-factor VIII immune responses in hemophilia A mice after factor VIII plasmid-mediated gene therapy Blood, November 12, 2009; 114(20): 4373 - 4382. [Abstract] [Full Text] [PDF] M. van den Biggelaar, E. A.M. Bouwens, N. A. Kootstra, R. P. Hebbel, J. Voorberg, and K. Mertens Storage and regulated secretion of factor VIII in blood outgrowth endothelial cells Haematologica, May 1, 2009; 94(5): 670 - 678. [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] B. Gangadharan, E. T. Parker, L. M. Ide, H. T. Spencer, and C. B. Doering High-level expression of porcine factor VIII from genetically modified bone marrow-derived stem cells Blood, May 15, 2006; 107(10): 3859 - 3864. [Abstract] [Full Text] [PDF] S. S. T.-D. Ravin, D. R. Kennedy, N. Naumann, J. S. Kennedy, U. Choi, B. J. Hartnett, G. F. Linton, N. L. Whiting-Theobald, P. F. Moore, W. Vernau, et al. Correction of canine X-linked severe combined immunodeficiency by in vivo retroviral gene therapy Blood, April 15, 2006; 107(8): 3091 - 3097. [Abstract] [Full Text] [PDF] Y. Kang, L. Xie, D. T. Tran, C. S. Stein, M. Hickey, B. L. Davidson, and P. B. McCray Jr Persistent expression of factor VIII in vivo following nonprimate lentiviral gene transfer Blood, September 1, 2005; 106(5): 1552 - 1558. [Abstract] [Full Text] [PDF] L. Xu, T. C. Nichols, R. Sarkar, S. McCorquodale, D. A. Bellinger, and K. P. Ponder Absence of a desmopressin response after therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy PNAS, April 26, 2005; 102(17): 6080 - 6085. [Abstract] [Full Text] [PDF] J. Schuettrumpf, R. W. Herzog, A. Schlachterman, A. Kaufhold, D. W. Stafford, and V. R. Arruda Factor IX variants improve gene therapy efficacy for hemophilia B Blood, March 15, 2005; 105(6): 2316 - 2323. [Abstract] [Full Text] [PDF] H. Z. Miao, N. Sirachainan, L. Palmer, P. Kucab, M. A. Cunningham, R. J. Kaufman, and S. W. Pipe Bioengineering of coagulation factor VIII for improved secretion Blood, May 1, 2004; 103(9): 3412 - 3419. [Abstract] [Full Text] [PDF] D. Lillicrap Hemophilia gene therapy: it's a matter of expression Blood, January 1, 2004; 103(1): 5 - 6. [Full Text] [PDF] M. E. Rick, C. E. Walsh, and N. S. Key Congenital Bleeding Disorders Hematology, January 1, 2003; 2003(1): 559 - 574. [Abstract] [Full Text] [PDF]

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020