High expression reduces an antibody response after neonatal gene therapy with B domain-deleted human factor VIII in mice

L. Xu, M. Mei, X. Ma, Katherine P. Ponder

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29 Scopus citations


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 [1010 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.

Original languageEnglish
Pages (from-to)1805-1812
Number of pages8
JournalJournal of Thrombosis and Haemostasis
Issue number9
StatePublished - Sep 2007


  • Ffactor VIII
  • Hemophilia A
  • Inhibitor
  • Neonatal
  • Retroviral vector


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