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

Haemophilia A is a classic X-linked disease which affects 1 in 5–10, 000 males in all populations¹ and is caused by defects in coagulation factor VIII^{2, 3}. 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, includinggene therapy, have been proposed². Natural canine models of factor VIII and factor IX deficiency have been available for many years^4–5, and gene therapy attempts on these dogs have met with partial success^6–8. 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 factorVIII deficiency.