Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A

Abstract

Haemophilia A is a classic X-linked disease which affects 1 in 5-10,000 males in all populations and is caused by defects in coagulation factor VIII. Roughly 60% of patients have severe disease with factor VIII activity < 1% of normal; they have frequent spontaneous bleeding into joints, soft tissues, muscles and internal organs. These patients usually require regular injections of plasma-derived or recombinant human factor VIII. Because this is expensive and can potentially lead to life-threatening complications, other forms of therapy, including gene therapy, have been proposed. Natural canine models of factor VIII and factor IX deficiency have been available for many years, and gene therapy attempts on these dogs have met with partial success. However, a small animal model of the disease is desirable for studies of factor VIII function and gene therapy. Using gene targeting, we have made a mouse with severe factor VIII deficiency.

Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation

“…These mice have a targeted disruption of FVIII exon 16 which results in an undetectable level of FVIII activity; such E16 mice have been used as a small animal model for severe hemophilia A [27]. E16 mice (n = 8-10 animals/-group) were treated weekly for 5 weeks with test SVP or control empty NP through i.v.…”

Suppression of FVIII Inhibitor Formation in Hemophilic Mice by Delivery of Transgene Modified Apoptotic Fibroblasts

“…Studies were performed on 8-12-week-old exon 16 knockout hemophilia A mice in the 129SV background strain. 38 Mice were housed under specific pathogen-free conditions in a University of Washington animal facility and studied in accordance with an Institutional Animal Care and Use Committee approved protocol. Blood was obtained by cardiac puncture or tail nick, anticoagulated with 0.1 mol/l sodium citrate at a 9:1 (vol/vol) ratio.…”

Phenotypic correction of murine hemophilia A using an iPS cell-based therapy

“…All animal studies were performed following National Institutes of Health guidelines and approved by the Institutional Animal Care and Use Committee at Nevada Cancer Institute. Six hemophilia A mice (Jackson Laboratory, strain name: B6; 129S4-F8tm1Kaz/J, stock number: 004424) 6 -8 weeks old were used for this study (28). Hemophilia A mice were produced originally by disruption of the FVIII gene through insertion of a targeting vector containing a neomycin gene cassette in the 3Ј end of exon 16 (28).…”