Gene therapy of the hemophilias.

Development of hemophilia gene therapy depends on testing gene transfer vectors in hemophilic and nonhemophilic animals. Available animal models include factor VIII or factor IX knockout mice as well as dogs with spontaneous hemophilia A or B. Large animals (particularly dogs) more closely replicate the requirements for correction of human hemophilia than do mice. Small animals are more convenient to maintain and require significantly less vector for testing than do large animals. Nonhemophilic animals (mice or nonhuman primates), whose endogenous factor VIII and factor IX complicate analysis of the human proteins, have utility for safety testing of vectors; some assays can discriminate between human coagulation factors and the endogenous coagulation factors. Most animal models suffer the limitations imposed by the immune response to human factor VIII or IX protein. Clinical trials have failed to achieve significant factor VIII expression in hemophilia A patients, while one clinical trial in hemophilia B patients showed only transient therapeutic increments of factor IX expression. Gene therapy remains an investigational method with many obstacles to overcome before it can be widely used as treatment for hemophilia.