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 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. (Blood. 2000;95:2799-2805)
Fakharzadeh
S S
SS
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6145, USA. ssf@mail.med.upenn.edu
Zhang
Y
Y
Sarkar
R
R
Kazazian
H H
HH
D000818:Animals; D005169:Factor VIII / Q000096:biosynthesis / Q000235:genetics*; D016654:Genes, RAG-1; D015316:Genetic Therapy / Q000379:methods*; D006467:Hemophilia A / Q000628:therapy*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis; D016038:Skin Transplantation
D018398:Homeodomain Proteins; D011498:Protein Precursors; D011994:Recombinant Proteins; C064658:RAG-1 protein; C032253:involucrin; D005169:Factor VIII