SUSTAINED PHENOTYPIC CORRECTION OF MURINE HEMOPHILIA-A BY IN-VIVO GENE-THERAPY

Hemophilia A is caused by a deficiency of blood coagulation factor VII I (FVIII) and has been widely discussed as a candidate for gene therap y, While the natural canine model of hemophilia A has been valuable fo r the development of FVIII pharmaceutical products, the use of hemophi liac dogs for gene therapy studies has several limitations such as exp ense and the long canine generation time. The recent creation of two s trains of FVIII-deficient mice provides the first small animal model o f hemophilia A, Treatment of hemophiliac mice of both genotypes with p otent, human FVIII-encoding adenoviral vectors resulted in expression of biologically active human FVIII at levels, which declined, but rema ined above the human therapeutic range for over 9 months. The duration of expression and FVIII plasma levels achieved were similar in both h emophiliac mouse strains. Treated mice readily survived tail clipping with minimal blood loss, thus showing phenotypic correction of murine hemophilia A by in vivo gene therapy. (C) 1998 by The American Society of Hematology.