Correction of the coagulation defect in hemophilia A mice through factor VIII expression in skin

To test the hypothesis that factor VIII expressed in the epidermis can corr ect hemophilia A, we generated transgenic mice in a factor VIII-deficient b ackground that express human factor VIII under control of the involucrin pr omoter. Mice from 5 transgenic lines had both phenotypic correction and pla sma factor VIII activity. In addition to the skin, however, some factor VII I expression was detected in other tissues that have stratified squamous ep ithelia, To determine whether an exclusively cutaneous source of factor VII I could correct factor VIII deficiency, we grafted skin explants from trans genic mice onto mice that are double knockouts for the factor VIII and RAG- 1 genes. Two graft recipients had plasma factor VIII activity of 4% to 20% of normal and improved whole blood clotting compared with factor VIII-defic ient mice. Thus, expression of factor VIII from the epidermis can correct h emophilia A mice, thereby supporting the feasibility of cutaneous gene ther apy for systemic disease, (Blood. 2000;95:2799-2805) (C) 2000 by The Americ an Society of Hematology.