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Blood, 1 November 2005, Vol. 106, No. 9, pp. 3043-3048. Prepublished online as a Blood First Edition Paper on July 28, 2005; DOI 10.1182/blood-2005-03-1307. This Article Full Text (PDF) All Versions of this Article: 2005-03-1307v1 106/9/3043    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 James, P. D Articles by Lillicrap, D. Search for Related Content PubMed PubMed Citation Articles by James, P. D Articles by Lillicrap, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 5, 2005 Accepted June 30, 2005 Aminoglycoside suppression of nonsense mutations in severe hemophilia Paula D James, Sanj Raut, Georges E Rivard, Man-Chiu Poon, Margaret Warner, Susan McKenna, Jayne Leggo, and David Lillicrap* Department of Medicine, Queen's University, Kingston, Ontario, Canada National Institute for Biological Standards and Control, Potter's Bar, United Kingdom Department of Hematology, Hopital Sainte-Justine, Montreal, Quebec, Canada Departments of Medicine, Pediatrics and Oncology, University of Calgary, Calgary, Alberta, Canada Department of Medicine, McGill University, Montreal, Quebec, Canada Department of Pharmacy, Queen's University, Kingston, Ontario, Canada Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada * Corresponding author; email: lillicrap{at}cliff.path.queensu.ca. Aminoglycoside antibiotics exhibit their bactericidal effect by interfering with normal ribosomal activity. In this pilot study, we have evaluated the effect of the aminoglycoside antibiotic, gentamicin, on the factor VIII and IX levels of severe hemophiliacs with known nonsense mutations. Five patients were enrolled and each patient was given 3 consecutive days of gentamicin at a dose of 7mg/kg IV q24h. Two patients (Patient #1 Hemophilia A Ser1395Stop and Patient #5 Hemophilia B Arg333Stop) showed a decrease in their aPTT, an increase in their FVIII (0.016 IU/mL - 1.6%) or FIX (0.02 IU/mL - 2%) levels and an increase in thrombin generation. The remaining three patients (Patient #2 Hemophilia B Arg252Stop, Patient #3 Hemophilia A Arg2116Stop and Patient #4 Hemophilia A Arg427Stop) showed no response in the aPTT or factor levels, but one (Patient #2 Hemophilia B Arg252Stop) showed an increase in the factor IX antigen level (2-5.5%) that persisted throughout the period of the study and was concordant with an increase in thrombin generation. Gentamicin is unlikely to be an effective treatment for severe hemophilia due to its potential toxicities, and the minimal response documented in this report. This study, however, does provide a proof-of-principle, suggesting that ribosomal interference with a less toxic agent may be a potential therapeutic mechanism for severe hemophilia patients with nonsense mutations. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Yang, J. Feng, W. Song, J. Wang, B. Tsai, Y. Zhang, W. A. Scaringe, K. A. Hill, P. Margaritis, K. A. High, et al. A mouse model for nonsense mutation bypass therapy shows a dramatic multiday response to geneticin PNAS, September 25, 2007; 104(39): 15394 - 15399. [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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