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Blood, Vol. 95 No. 9 (May 1), 2000:
pp. 2799-2805
Correction of the coagulation defect in hemophilia A mice
through factor VIII expression in skin
Steven S. Fakharzadeh,
Yue Zhang,
Rita Sarkar, and
Haig H. Kazazian Jr
From the Departments of Genetics and Dermatology, University of
Pennsylvania School of Medicine, Philadelphia, PA.
To test the hypothesis that factor VIII expressed in the epidermis
can correct hemophilia A, we generated transgenic mice in a factor
VIII-deficient background that express human factor VIII under control
of the involucrin promoter. Mice from 5 transgenic lines had both
phenotypic correction and plasma factor VIII activity. In addition to
the skin, however, some factor VIII expression was detected in other
tissues that have stratified squamous epithelia. To determine whether
an exclusively cutaneous source of factor VIII could correct factor
VIII deficiency, we grafted skin explants from transgenic 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-deficient mice. Thus, expression of factor VIII from the
epidermis can correct hemophilia A mice, thereby supporting the
feasibility of cutaneous gene therapy for systemic disease.
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