Induction of tolerance to human factor VIII in mice.

Blood
H Chao, C E Walsh

Abstract

This paper reports loss of human factor VIII (hFVIII) inhibitory antibody in immunocompetent C57BL/6 mice. High-titer anti-hFVIII antibody developed in the mice within 7 to 14 days of intraportal administration of adeno-associated virus (AAV) carrying FVIII that coincided with a reduction in plasma hFVIII antigen. Bethesda titers (> 100 units) persisted relatively unchanged for 9 to 10 months. Unexpectedly, at 10 months after injection of the virus, hFVIII protein (up to 59 ng/mL) was detected in 3 mice at the same time as disappearance of hFVIII inhibitor. The level of hFVIII was similar to that found in immunodeficient mice receiving the same dose of recombinant AAV carrying hFVIII without hFVIII inhibitor. These results suggest that tolerance to hFVIII can be induced by sustained expression of hFVIII in a mouse model. Further elucidation of this observation may affect use of FVIII gene transfer in the treatment of inhibitor-positive patients with hemophilia A.

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Citations

Jan 8, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Lingxia ChenWeidong Xiao
Nov 18, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·Mark J OsbornBruce R Blazar
Feb 1, 2003·Haemophilia : the Official Journal of the World Federation of Hemophilia·A Van DammeT VandenDriessche
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Nov 24, 2005·Clinical Medicine & Research·Eric Dobrzynski, Roland W Herzog
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Oct 14, 2004·Haemophilia : the Official Journal of the World Federation of Hemophilia·M K L ChuahT Vandendriessche
Jun 11, 2005·Journal of Thrombosis and Haemostasis : JTH·C Hough, D Lillicrap
Jun 29, 2004·Journal of Thrombosis and Haemostasis : JTH·P Lollar
Dec 17, 2003·Journal of Thrombosis and Haemostasis : JTH·D A WilcoxR R Montgomery
Nov 25, 2006·Haemophilia : the Official Journal of the World Federation of Hemophilia·W K Hoots
Sep 18, 2010·The Journal of Gene Medicine·Inge PetrusThierry VandenDriessche
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Jan 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Chuhong HuGerald S Lipshutz
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Sep 1, 2004·Molecular Therapy : the Journal of the American Society of Gene Therapy·Thomas J SferraYan Hu
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