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

Author:

Fakharzadeh Steven S.1,Zhang Yue1,Sarkar Rita1,Kazazian Haig H.1

Affiliation:

1. From the Departments of Genetics and Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA.

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference36 articles.

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3. Genetically modified skin to treat disease: potential and limitations.;Krueger;J Invest Dermatol.,1994

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5. Tissue- and stratum-specific expression of the human involucrin promoter in transgenic mice.;Carroll;Proc Natl Acad Sci U S A.,1993

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