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  • Title: High expression reduces an antibody response after neonatal gene therapy with B domain-deleted human factor VIII in mice.
    Author: Xu L, Mei M, Ma X, Ponder KP.
    Journal: J Thromb Haemost; 2007 Sep; 5(9):1805-12. PubMed ID: 17596134.
    Abstract:
    BACKGROUND: Gene therapy could prevent bleeding in patients with hemophilia A, but might induce antibodies that block factor VIII (FVIII) function. OBJECTIVES: To test the efficacy of gene therapy in the newborn period for preventing a response to human FVIII (hFVIII) because of immaturity of the immune system. METHODS: Varying doses of a retroviral vector (RV) expressing a B domain-deleted hFVIII cDNA were injected i.v. into newborn hemophilia A C57BL/6 or normal C3H mice. Mice were evaluated for hFVIII expression, hemostasis, and development of anti-hFVIII antibodies with inhibitory activity. RESULTS AND CONCLUSIONS: Injection of a high RV dose [10(10) transducing units (TU) kg(-1)] into newborn hemophilia A or C3H mice resulted in 61% and 13% of normal hFVIII antigen in plasma, respectively; most mice did not produce anti-hFVIII antibodies, and hemophilia A mice did not bleed. Furthermore, most mice with >20 ng mL(-1) of hFVIII in plasma (10% normal, 1 x 10(-10) m) were tolerant to hFVIII, as an antibody response was markedly reduced after challenge with hFVIII with or without adjuvant. However, most RV-treated animals with lower antigen levels developed antibodies before or after challenge. Thus, initiation of a gene therapy trial with low RV doses might increase inhibitor formation. Furthermore, frequent hFVIII infusions in newborns with hemophilia A might reduce inhibitor formation. Finally, difficulties in achieving tolerance after gene therapy for hemophilia A as compared to hemophilia B may relate to lower expression of FVIII than FIX, as high antigen levels are most effective at inducing tolerance.
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