Hemophilia A is a hereditary disorder caused by various mutations in
factor VIII gene resulting in either a severe deficit or total lack of the corresponding activity. Recent success in gene therapy of a related disease,
hemophilia B, gives new hope that similar success can be achieved for
hemophilia A as well. To develop a gene
therapy strategy for the latter, a variety of model systems are needed to evaluate molecular engineering of the
factor VIII gene, vector delivery efficacy and safety-related issues. Typically, a tissue culture cell line is the most convenient way to get a preliminary glimpse of the potential of a vector delivery strategy. It is then followed by extensive testing in
hemophilia A mouse and dog models. Newly developed
hemophilia A sheep may provide yet another tool for evaluation of
factor VIII gene delivery vectors.
Hemophilia models based on other species may also be developed since hemophiliac animals have been identified or generated in rat, pig, cattle and horse. Although a genetic nonhuman primate
hemophilia A model has yet to be developed, the non-genetic
hemophilia A model can also be used for special purposes when specific questions need to be addressed that cannot not be answered in other model systems.
Hemophilia A is caused by a functional deficiency in the
factor VIII gene. This X-linked, recessive
bleeding disorder affects approximately 1 in 5000 males [1-3]. Clinically, it is characterized by frequent and spontaneous joint
hemorrhages, easy bruising and prolonged bleeding time. The coagulation activity of FVIII dictates severity of the clinical symptoms. Approximately 50% of all cases are classified as severe with less than 1% of normal levels of
factor VIII detected [4]. This deficiency may lead to spontaneous joint
hemorrhages or life-threatening
bleeding. In contrast, patients with 5-30% of normal
factor VIII activity exhibit mild clinical manifestations.