title: Aminoglycoside suppression of nonsense mutations in severe hemophilia.
abstract: 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 (FVIII) 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 7 mg/kg intravenously every 24 hours. Two patients (patient no. 1: hemophilia A, Ser1395Stop; and patient no. 5: hemophilia B, Arg333Stop) showed a decrease in their activated partial thromboplastin time (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 3 patients (patient no. 2: hemophilia B, Arg252Stop; patient no. 3: hemophilia A, Arg2116Stop; and patient no. 4: hemophilia A, Arg427Stop) showed no response in the aPTTs or factor levels, but one (patient no. 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.
authors.affiliation: Department of Medicine, Queen's University, Kingston, Ontario, Canada K7L 3N6.
authors.forename: Paula D
authors.initials: PD
authors.lastname: James
authors.forename: Sanj
authors.initials: S
authors.lastname: Raut
authors.forename: Georges E
authors.initials: GE
authors.lastname: Rivard
authors.forename: Man-Chiu
authors.initials: MC
authors.lastname: Poon
authors.forename: Margaret
authors.initials: M
authors.lastname: Warner
authors.forename: Susan
authors.initials: S
authors.lastname: McKenna
authors.forename: Jayne
authors.initials: J
authors.lastname: Leggo
authors.forename: David
authors.initials: D
authors.lastname: Lillicrap
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D018389:Codon, Nonsense / Q000235:genetics*; D005164:Factor IX / Q000378:metabolism; D005169:Factor VIII / Q000378:metabolism; D005839:Gentamicins / Q000494:pharmacology; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D010314:Partial Thromboplastin Time
chemical_list: D000617:Aminoglycosides; D018389:Codon, Nonsense; D005839:Gentamicins; D005169:Factor VIII; D005164:Factor IX